chr13-51949700-C-T

Position:

chr13-51949700-C-T

Variant summary

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

The NM_000053.4(ATP7B):c.2827G>A(p.Gly943Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,754 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.85

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 Extracellular (size 29) in uniprot entity ATP7B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 13-51949700-C-T is Pathogenic according to our data. Variant chr13-51949700-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2827G>A	p.Gly943Ser	missense_variant	12/21	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.2827G>A	p.Gly943Ser	missense_variant	12/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249320

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 943 of the ATP7B protein (p.Gly943Ser). This variant is present in population databases (rs28942076, gnomAD 0.007%). This missense change has been observed in individuals with Wilson disease (PMID: 7626145, 11243728, 27022412). ClinVar contains an entry for this variant (Variation ID: 3856). 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) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 10942420). This variant disrupts the p.Gly943 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16088907, 16603785, 27930511, 28212618). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 14, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 22, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 16, 2016	Variant summary: c.2827G>A affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 2/120362 control chromosomes at a frequency of 0.0000166, which does not exceed maximal expected frequency of a pathogenic allele (0.0054006). This variant has been reported in multiple affected individuals and functional studies showed that variant had impaired ability to complement the high-affinity iron-uptake deficiency of the yeast mutant, and despite the normal localization of variant to the Golgi network of CHO cells, variant was non-responsive to copper and exhibited no obvious copper-induced redistribution (Forbes_1998 and 2000). Taken together, this variant was classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Gly943Ser variant in ATP7B has been identified in multiple indivduals with Wilson diease, including at least 3 homozygotes or compound heterozygotes, and segregated with disease in 1 affected relative (Figus 1995, Thomas 1995, Butler 2001, Margarit 2005, Park 2007, Zhang 2016). It has also been identified in 0.006% (1/15464) of African chromosomes in gnomAD (https://gnomad.broadinstitute.org/) and reported in ClinVar (Variation ID 3856). In vivo functional studies in yeast support an impact on protein function (Forbes 2000). An additional pathogenic variant involving this codon (p.Gly943Asp) has also been identified in individuals with Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM3_Strong, PM2, PM5, PP1, PP4, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATP7B: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 30, 2020	PS3, PS4_moderate, PM2, PP1, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

D;D;.;.;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.6

D;D;D;D;.;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;D;D;.;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

1.0

D;D;B;D;D;D

Vest4

0.91

MutPred

0.90

Gain of helix (P = 0.062);.;.;.;.;Gain of helix (P = 0.062);

MVP

1.0

MPC

0.38

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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