rs181250704

Positions:

chr13-51935019-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000053.4(ATP7B):c.4135C>T(p.Pro1379Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00192 in 1,613,790 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 5 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:3

Conservation

PhyloP100: 5.00

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05517918).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.4135C>T	p.Pro1379Ser	missense_variant	21/21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.4135C>T	p.Pro1379Ser	missense_variant	21/21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

228

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

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:

0.00243

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00113

AC:

279

AN:

247004

Hom.:

AF XY:

0.00109

AC XY:

147

AN XY:

134252

show subpopulations

Gnomad AFR exome

AF:

0.000453

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00196

AC:

2871

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1349

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00161

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00240

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.00149

AC:

227

AN:

152174

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00243

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.00164

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000498

AC:

ESP6500EA

AF:

0.00215

AC:

ExAC

AF:

0.00108

AC:

131

EpiCase

AF:

0.00251

EpiControl

AF:

0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Uncertain:8Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 12, 2022	This missense variant replaces proline with serine at codon 1379 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). However, functional studies have shown that this variant did not impact protein expression, copper transport and trafficking, and oxidase activity (PMID: 14962673, 21454443). This variant has been observed in the compound heterozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 16088907, 23430806, 32685348). This variant has been identified in 311/278336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces proline with serine at codon 1379 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant had normal protein expression, copper transport and trafficking, and oxidase activity; similar to wild-type (PMID: 14962673, 21454443). This variant has been observed in many individuals affected with autosomal recessive Wilson disease (PMID: 16088907, 23430806, 32685348) all of which are compound heterozygous. This variant has been identified in 311/278336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 20, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	The ATP7B c.4135C>T; p.Pro1379Ser variant (rs181250704) is reported in the literature in an individual with Wilson disease (Cox 2005). This variant was detected in trans with a pathogenic variant in four children from two families (Bennett 2013; Yi 2020); since there is significant variation in age of presentation in patients with Wilson disease (Weiss 2016), it is difficult to assess the significance of the reports of unaffected children currently. Functional analyses show the variant protein has normal transport activity (Braiterman 2011). This variant is listed in ClinVar (Variation ID: 157957), and is found in the general population with an overall allele frequency of 0.11% (311/278,336 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.879). Although some evidence suggests ATP7B p.Pro1379Ser is not a deleterious variant, due limited clinical information on children harboring this variant in trans to a pathogenic ATP7B variant, its clinical significance cannot be determined with certainty at this time. References: Bennett JT et al. An exceptional family with three consecutive generations affected by Wilson disease. JIMD Rep. 2013;10:1-4. PMID: 23430806. Braiterman L et al. Critical roles for the COOH terminus of the Cu-ATPase ATP7B in protein stability, trans-Golgi network retention, copper sensing, and retrograde trafficking. Am J Physiol Gastrointest Liver Physiol. 2011 Jul;301(1):G69-81. PMID: 21454443. Cox DW et al. Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Hum Mutat. 2005 Sep;26(3):280. PMID: 16088907. Weiss KH. Wilson Disease. 1999 Oct 22 [Updated 2016 Jul 29]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1512 Yi F et al. p.P1379S, a benign variant with reduced ATP7B protein level in Wilson Disease. JIMD Rep. 2020 May 19;54(1):32-36. PMID: 32685348. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Mar 24, 2017	- -

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ATP7B: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2024	Functional analysis found that it is associated with normal transport activity and trafficking (PMID: 21454443); 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: 14962673, 28392828, 25741868, 16472602, 33848968, 32685348, 17680703, 32248359, 34426522, 24253677, 30254379, 30097039, 23430806, 35626323, 34620762, 16088907, 21454443, 37660282, 33972609, 37937776, 30476936) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 08, 2019	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2022	Variant summary: ATP7B c.4135C>T (p.Pro1379Ser) results in a non-conservative amino acid change located in the after the TM8 domain (Tang_2019) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 247012 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0011 vs 0.0054), allowing no conclusion about variant significance. c.4135C>T has been reported in the literature in at-least one individual affected with Wilson Disease (Cox_2005) and as a compound heterozygote in an unaffected newborn with a genotype (H1069Q/P1379S) from a family in which the affected proband was homozygous for the other well reported variant (H1069Q/H1069Q) (Bennett_2013). It was also reported in a study among individuals who had no family history or indications of of WD (Collet_2018). Additionally, it was found in four compound heterozygous children with one known pathogenic variant and remain asymptomatic without abnormal laboratory consequences (Yi_2020). Lastly, this variant has been reported in a recent study describing the global prevalence of Wilson disease as one among five most frequently known disease variants citing Cox_2005 (Gao_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on copper transport, protein stability or copper-responsive trafficking (Braiterman_2011). 13 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=11) and likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2017

The p.P1379S variant (also known as c.4135C>T), located in coding exon 21 of the ATP7B gene, results from a C to T substitution at nucleotide position 4135. The proline at codon 1379 is replaced by serine, an amino acid with similar properties. This alteration was first described in an Italian patient diagnosed with Wilson disease; however, a second pathogenic alteration was not described (Cox DW et al. Hum. Mutat., 2005 Sep;26:280). In another study, p.P1379S was confirmed in trans with a pathogenic mutation in a child who, at 21 months was healthy, developing normally, and had normal ceruloplasmin levels (Bennett JT et al. JIMD Rep, 2013 Mar;10:1-4). A functional assay, using an hepatoma-derived hybrid cell line (WIF-B), showed that P1379S resulted in no dramatic defect in copper transport, protein stability, or copper-responsive trafficking when compared to wild-type (Braiterman L et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2011 Jul;301:G69-81). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

ATP7B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

The ATP7B c.4135C>T variant is predicted to result in the amino acid substitution p.Pro1379Ser. This variant has been reported in the heterozygous state in an individual with Wilson disease, but it was unclear if a second causative allele was identified (Cox et al. 2005. PubMed ID: 16088907). It has also been reported in the compound heterozygous state in a child with suspected Wilson disease (Bennett et al. 2013. PubMed ID: 23430806). This variant has been reported as disease causing in a French cohort (Collet et al. 2018. PubMed ID: 30097039) and a meta-analysis of Wilson disease studies (Gao et al. 2019. PubMed ID: 30254379). However, functional studies suggest that this variant does not impact copper transport, protein stability, or copper-responsive trafﬁcking (Braiterman et al. 2011. PubMed ID: 21454443). In ClinVar, the vast majority of clinical laboratories interpret this variant as uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/157957/). At this time, the clinical significance of this variant is uncertain due to due to the lack of conclusive functional and genetic evidence. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 23, 2021

ACMG classification criteria: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.055

T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.7

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

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.1

D;D;D;D;D;.;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

D;D;D;D;D;.;D

Sift4G

Uncertain

0.0060

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

Polyphen

1.0

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

Vest4

0.28

MVP

0.99

MPC

0.35

ClinPred

0.091

GERP RS

5.7

Varity_R

0.36

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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