rs186924074

Positions:

chr13-51961861-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP3BS2_Supporting

The NM_000053.4(ATP7B):c.1922T>C(p.Leu641Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000828 in 1,614,082 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L641V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 2 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 8.39

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 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000053.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.1922T>C	p.Leu641Ser	missense_variant	6/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.1922T>C	p.Leu641Ser	missense_variant	6/21	1	NM_000053.4	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.000941

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000489

AC:

122

AN:

249584

Hom.:

AF XY:

0.000473

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000768

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000854

AC:

1248

AN:

1461766

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

583

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000584

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000863

Hom.:

Bravo

AF:

0.000669

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000524

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.000397

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Uncertain:6Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces leucine with serine at codon 641 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 does not impact protein expression, copper transport activity, and binding to COMMD1 (PMID: 17919502, 24706876). This variant has been reported in individuals affected with Wilson disease (PMID: 15967699, 16088907, 22677543, 23518715, 30232804, 34400371) as well as in unaffected individuals (PMID: 30097039, 34620762). This variant has been identified in 130/280986 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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 641 of the ATP7B protein (p.Leu641Ser). This variant is present in population databases (rs186924074, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease (PMID: 15967699, 16088907, 22677543, 23518715, 34400371). ClinVar contains an entry for this variant (Variation ID: 420002). 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 does not substantially affect ATP7B function (PMID: 17919502, 24706876). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2022	The ATP7B c.1922T>C; p.Leu641Ser variant (rs186924074) is reported in the literature in individuals affected with Wilson disease (Bost 2012, Coffey 2013, Cox 2005, Vrabelova 2005). This variant is reported in ClinVar (Variation ID: 420002), and is found in the general population with an overall allele frequency of 0.046% (130/280986 alleles) in the Genome Aggregation Database. The leucine at codon 641 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.93). However, functional analyses of the variant protein show similar copper trafficking compared to wild type (Braiterman 2014, de Bie 2007). Due to conflicting information, the clinical significance of the p.Leu641Ser variant is uncertain at this time. 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;26(2-3):97-101. PMID: 22677543. Braiterman LT et al. Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B. Proc Natl Acad Sci U S A. 2014;111(14):E1364-E1373. PMID: 24706876. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013;136(Pt 5):1476-1487. PMID: 23518715. Cox DW et al. Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Hum Mutat. 2005;26(3):280. PMID: 16088907. de Bie P et al. Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology. 2007;133(4):1316-1326. PMID: 17919502. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005;86(1-2):277-285. PMID: 15967699. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_000053.3(ATP7B):c.1922T>C(L641S) is a missense variant classified as a variant of uncertain significance in the context of Wilson disease. L641S has been observed in cases with relevant disease (PMID: 30232804, 15967699, 16088907, 22677543). Functional assessments of this variant are available in the literature (PMID: 24706876, 17919502). L641S has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_000053.3(ATP7B):c.1922T>C(L641S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated that p.(L641S) behaved similarly to the wild-type protein (de Bie et al. 2007; Braiterman et al. 2014); This variant is associated with the following publications: (PMID: 15967699, 23518715, 17919502, 18371106, 22677543, 24253677, 30097039, 34426522, 32248359, 16088907, Cumpata2022[Review], 24706876, 34400371, 36096368, 34620762, 35132767) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 14, 2021

Variant summary: ATP7B c.1922T>C (p.Leu641Ser) results in a non-conservative amino acid change in 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 0.0005 in 251632 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0005 vs 0.0054), allowing no conclusion about variant significance. The variant c.1922T>C has been reported in the literature in individuals affected with Wilson Disease (example: Cox_2005, Vrabelova_2005, Bost_2012, Ferenci_2019), however, in most of these cases no full gene sequencing was performed, and/or the other pathogenic variant in trans was not specified and/or phase was not provided. These data therefore do not allow clear conclusions about the variant significance. Publications also reported experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on protein localization, copper transport activity, and copper-responsive trafficking (Braiterman_2014) and no effect on interaction with COMMD1 (de Bie_2007). Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) or likely benign (n=2). 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

Sep 30, 2022

The c.1922T>C (p.L641S) alteration is located in exon 6 (coding exon 6) of the ATP7B gene. This alteration results from a T to C substitution at nucleotide position 1922, causing the leucine (L) at amino acid position 641 to be replaced by a serine (S). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.L641 amino acid is conserved in available vertebrate species. The p.L641S alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;T;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.4

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;N

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.8

D;D;D;.;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;T;D;.;D

Sift4G

Uncertain

0.019

D;D;D;D;D

Polyphen

1.0

D;D;B;P;D

Vest4

0.81

MVP

0.95

MPC

0.42

ClinPred

0.23

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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