rs121907994

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.2621C>T(p.Ala874Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18U:1

Conservation

PhyloP100: 9.89

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 133) in uniprot entity ATP7B_HUMAN there are 18 pathogenic changes around while only 3 benign (86%) in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 13-51950116-G-A is Pathogenic according to our data. Variant chr13-51950116-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51950116-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2621C>T	p.Ala874Val	missense_variant	11/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2621C>T	p.Ala874Val	missense_variant	11/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000681

AC:

AN:

249574

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

135402

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000445

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000831

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000718

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000745

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:14Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 874 of the ATP7B protein (p.Ala874Val). This variant is present in population databases (rs121907994, gnomAD 0.05%). This missense change has been observed in individuals with Wilson disease, with evidence of co-segregation with disease (PMID: 10544227, 10721669, 11775208, 12376745, 12544487, 16998622, 18156766, 21707886, 22735241). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3851). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, flagged submission	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Likely pathogenic, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2018	Variant summary: ATP7B c.2621C>T (p.Ala874Val) results in a non-conservative amino acid change in the P-type ATPase, A domain superfamily 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 6.9e-05 in 246236 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.9e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.2621C>T, has been reported in the literature in multiple individuals affected with Wilson Disease in both compound heterozygotes and homozygotes (Lee_2011, Dong_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function evaluating copper transport. The most pronounced variant effect results in 10-30% of normal copper transport rate activity (Huster_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces alanine with valine at codon 874 in the actuator domain 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 causes reduced protein expression, abnormal subcellular localization, and loss of copper transport activity (PMID: 22240481, 22692182). This variant has been reported in individuals affected with Wilson disease (PMID: 10544227, 10721669, 11043508, 12376745, 12544487, 16998622, 18156766, 21645214, 21707886, 22735241, 26269689, 25988284, 27022412, 27398169, 28212618, 29381936, 30702195, 31980526, 33763395). In many of these individuals, this variant was reported in the compound heterozygous state (PMID: 12376745, 21645214, 28212618, 29381936, 30702195, 31743419, 33763395) or homozygous state (PMID: 10721669, 18156766, 21645214, 22735241, 30702195). This variant has been identified in 17/249574 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Ala874Val variant in ATP7B has been previously reported in many individuals with Wilson disease, including at least 2 compound heterozygotes and >10 compound heterozygotes, and segregated in at least 1 affected sibling (Chen 2019, Dong 2016, Kusuda 2000, Mihaylova 2012, Park 2009, Takeshita 2002, Tatsumi 2011, Yamaguchi 1998, Yoo 2002). It has been identified in 0.04% (8/17978) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, an in vitro functional study indicates that this variant results in reduced copper transport activity (Huster 2012). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PS3_Supporting, PP1, PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 20, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2020	Published functional studies using the baculovirus expression system in Sf9 cells showed partial transport activity (Huster et al. 2012); 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: 30275481, 31980526, 31743419, 9452121, 30702195, 30655162, 29961769, 11775208, 21707886, 10544227, 12544487, 27398169, 16998622, 22735241, 11043508, 28515472, 16207219, 25704634, 23275100, 22308153, 22484412, 26782526, 19419418, 29381936, 28212618, 26269689, 22692182, 10721669, 22240481, 24253677, 26215059, 25988284, 12376745, 18156766) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.5

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

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0040

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

Sift4G

Uncertain

0.0040

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.97

Gain of sheet (P = 0.0827);.;.;.;.;.;Gain of sheet (P = 0.0827);

MVP

0.93

MPC

0.35

ClinPred

0.78

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.87

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