rs201738967

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3PP5

The NM_000053.4(ATP7B):c.122A>G(p.Asn41Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000614 in 1,614,114 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00065 ( 2 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22U:1

Conservation

PhyloP100: 6.72

Variant links:

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a mutagenesis_site Altered copper-induced relocalization. (size 0) in uniprot entity ATP7B_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

PP5

Variant 13-51975098-T-C is Pathogenic according to our data. Variant chr13-51975098-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157928.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=12, Uncertain_significance=1, Pathogenic=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.122A>G	p.Asn41Ser	missense_variant	Exon 2 of 21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.122A>G	p.Asn41Ser	missense_variant	Exon 2 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000241

AC:

AN:

249446

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

135330

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000486

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000653

AC:

955

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

459

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000808

Gnomad4 OTH exome

AF:

0.000844

GnomAD4 genome

AF:

0.000237

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000332

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000485

AC:

ExAC

AF:

0.000232

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:14Uncertain:1

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces asparagine with serine at codon 41 of the ATP7B protein. This variant is located in the p.Phe37_Glu45 sequence that is thought to be an essential apical targeting determinant for ATP7B in elevated copper condition and participate in the post-trans-Golgi network retention of the protein under low-copper condition (PMID: 19033537). Functional studies have shown that this variant results in reduced protein stability and defective copper-induced trafficking of ATP7B protein (PMID: 19033537, 37660282, 38032054). This variant has been observed in many individuals affected with autosomal recessive Wilson disease with at least four individuals confirmed to carry this variant in compound heterozygosity with a second pathogenic variant (PMID: 15024742, 22677543, 22820477, 23518715, 32770663, 33640437, 36096368; DOI: 10.21203/rs.3.rs-2858430/v1, 10.12996/gmj.2023.3795; ClinVar Accession: SCV000626829.6). This variant has been identified in 68/280840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jul 01, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP7B c.122A>G (p.Asn41Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 249566 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00024 vs 0.0054), allowing no conclusion about variant significance. c.122A>G has been reported in the literature in individuals affected with Wilson Disease (e.g. Deguti_2004, Ben-Rebah_2012, Bost_2012,Coffey_2013, Woimant_2020, Collins_2021, Zhang_2022, Internal data). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and suggests that the variant impairs copper-sensitive ATP7B protein targeting and retention (Braiterman_2009). The following publications have been ascertained in the context of this evaluation (PMID: 20437613, 22106832, 22677543, 21454443, 19033537, 22820477, 23518715, 33640437, 15024742, 29473088, 22898812, 31408533, 32770663, 35220961). ClinVar contains an entry for this variant (Variation ID: 157928). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 25, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces asparagine with serine at codon 41 of the ATP7B protein. This variant is located in the p.Phe37_Glu45 sequence that is thought to be an essential apical targeting determinant for ATP7B in elevated copper condition and participate in the post-trans-Golgi network retention of the protein under low-copper condition (PMID: 19033537). A functional study has reported that this variant results in defective copper-induced trafficking of ATP7B protein in hepatic cells (PMID: 19033537). This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 15024742, 22677543, 22820477, 23518715, 32770663, 33640437, 36096368; ClinVar: SCV000626829.6), including at least six individuals in the compound heterozygous state or unknown phase with a second pathogenic variant in the ATP7B gene (PMID: 15024742, 22820477, 23518715, 33640437). This variant has been identified in 68/280840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 26, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.122A>G; p.Asn41Ser variant (rs201738967) has been described in at least 3 individuals affected with Wilson disease and two of these individuals carry a second pathogenic ATP7B variant (Bost 2012, Coffey 2013, Deguti 2004). It is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 157928) and observed in the general population at an overall frequency of 0.024% (68/280,840 alleles) in the Genome Aggregation Database. The asparagine at codon 41 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, in vitro functional analysis of this variant protein demonstrates severely disabled protein targeting and retention (Braiterman 2009). Based on available information, this variant is considered likely pathogenic. References: Bost M et al. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol. 2012 Jun;26(2-3):97-101. Braiterman L et al. Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B. Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G433-44. Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Deguti M et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The p.Asn41Ser variant in ATP7B has been reported in at least 3 heterozygous individuals and at least 2 compound heterozygous individuals with Wilson disease; though, 1 of these compound heterozygous individuals also carried a variant of uncertain significance in cis with the p.Asn41Ser (Deguti 2004 PMID: 15024742, Bost 2012 PMID: 22677543, Coffey 2013 PMID: 23518715, Zhao 2019 PMID: 30275481). It has also been identified in 0.047% (61/128586) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Braiterman 2009 PMID: 19033537). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PS3_Supporting. -

Jul 07, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in ATP7B is predicted to replace asparagine with serine at codon 41, p.(Asn41Ser). The asparagine residue is highly conserved (100 vertebrates, UCSC), and is located in the NXXY motif, a region that is shown to be critical for ATP7B protein transport (PMID: 19033537). There is a small physicochemical difference between asparagine and serine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.047% (61/128,586 alleles) in the European (non-Finnish) population. Computational evidence is uninformative for the missense substitution (REVEL = 0.569). This variant has been detected in at least four individuals with a clinical diagnosis of Wilson disease. These individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and were confirmed in trans (PMID:15024742, 23518715, 22820477, 33640437). Heterozygous variants in ATP7B have been reported in individuals with late-onset Parkinson's Disease and Wilson Disease (PMID: 31426520, 33972609). An in vitro functional assay using WIF-B cells and mutagenesis showed a complete disruption in protein trafficking in the basolateral membrane indicating that this variant impacts protein function, however, the reason for copper accumulation is still unknown (PMID: 19033537). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM1, PM2_Supporting, PS3_Supporting -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 41 of the ATP7B protein (p.Asn41Ser). This variant is present in population databases (rs201738967, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical and biochemical features of Wilson disease (PMID: 15024742, 22677543, 23518715; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 157928). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 19033537, 21454443). For these reasons, this variant has been classified as Pathogenic. -

Aug 16, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.122A>G (p.Asn41Ser) missense variant has been reported in two studies in which it is found in a compound heterozygote state in a total of three patients with Wilson disease. In one of the three patients, the p.Asn41Ser variant was detected in cis with a second missense variant and a third missense variant in trans (Deguti et al. 2004; Coffey et al. 2013). The p.Asn41Ser variant was absent from 60 controls (Deguti et al. 2004) and is reported at a frequency of 0.00048 in the European American population of the Exome Sequencing Project. Functionally, Braiterman et al. (2009) demonstrated that the p.Asn41Ser variant protein was defective in proper targeting and retention in WIF-B cells, when compared to wild type. Based on the evidence, the p.Asn41Ser variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:6

Apr 28, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant is associated with impaired protein trafficking and apical targeting, supporting a damaging effect (PMID: 19033537); Reported previously in patients with Wilson disease who were heterozygous for another variant in the ATP7B gene, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 15024742, 23518715, 35220961); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20437613, 17919502, 21454443, 22677543, 23518715, 22898812, 31589614, 34426522, 32248359, 30275481, 30937429, 27377421, 28719003, 26740555, 27460824, 34620762, 34400371, 22820477, 30097039, 32770663, 22106832, 26986070, 33640437, 31408533, 29473088, 29063292, 31059521, 36096368, 37660282, 34405919, 15024742, 19033537, 35220961, 37895316, 37937776) -

Sep 18, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jan 08, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122A>G (p.N41S) alteration is located in exon 2 (coding exon 2) of the ATP7B gene. This alteration results from an A to G substitution at nucleotide position 122, causing the asparagine (N) at amino acid position 41 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.02% (68/280840) total alleles studied. The highest observed frequency was 0.05% (61/128586) of European (non-Finnish) alleles. The p.N41S variant has been identified in multiple patients with Wilson disease with a second pathogenic ATP7B variant detected in trans or phase unknown in at least four of the reported cases (Ben-Rebeh, 2012; Bost, 2012; Brunet, 2012; Coffey, 2013; Deguti, 2004; Woimant, 2020). This amino acid position is highly conserved in available vertebrate species. Functional studies showed the p.N41S variant impairs apical targeting, Golgi retention, and ATP7B trafficking in vitro (Braiterman, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

ATP7B-related disorder

Pathogenic:1

Sep 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATP7B c.122A>G variant is predicted to result in the amino acid substitution p.Asn41Ser. This variant has been reported, in the compound heterozygous state, in two patients affected with Wilson disease (Deguti et al. 2004. PubMed ID: 15024742; Coffey et al. 2013. PubMed ID: 23518715). In-vitro functional studies showed that this variant results in severely disabled protein targeting and retention (Braiterman et al., 2009. PubMed ID: 19033537). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/157928/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;T;.;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.0

M;.;M;M;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.4

N;N;D;N;N;.;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.014

D;T;T;D;D;.;D

Sift4G

Uncertain

0.018

D;D;D;D;D;D;D

Polyphen

0.95

P;D;D;D;D;D;D

Vest4

0.77

MVP

0.98

MPC

0.34

ClinPred

0.071

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over