chr13-51944246-C-T

Position:

chr13-51944246-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000053.4(ATP7B):c.3106G>A(p.Val1036Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 2.74

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:

ATP7B (HGNC:):

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36718446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.3106G>A	p.Val1036Ile	missense_variant	14/21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.3106G>A	p.Val1036Ile	missense_variant	14/21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000884

AC:

AN:

248858

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000798

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 28, 2024	This missense variant replaces valine with isoleucine at codon 1036 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts copper transport and cell growth (PMID: 26004889). This variant has been reported in individuals affected with Wilson disease (PMID: 19062534, 23333878). This variant has been identified in 23/280234 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	Labcorp Genetics (formerly Invitae), Labcorp	Sep 10, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1036 of the ATP7B protein (p.Val1036Ile). This variant is present in population databases (rs761147984, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease (PMID: 25390358). ClinVar contains an entry for this variant (Variation ID: 553574). 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 not expected to disrupt ATP7B protein function. Experimental studies have shown that this missense change affects ATP7B function (PMID: 26004889). 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	Counsyl	Nov 15, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	Aug 22, 2024	Hot-spot of length 17 amino-acids has 26 missense/in-frame variants (16 pathogenic variants, 10 uncertain variants and no benign), which qualifies as moderate pathogenic (PM1). GnomAD genomes homozygous allele count = 0 is less than 2 for AR gene ATP7B. GnomAD exomes homozygous allele count = 0 is less than 2 for AR gene ATP7B (PM2). Combined evidence strength is Supporting (score = 1).Supporting: UniProt Variants classifies this variant as Pathogenic (PP5). MetaRNN = 0.367 is between 0.267 and 0.43 ⇒ supporting benign (BP4). We identified this variant in a 39-year-old woman with cholestasis. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 27, 2024

Variant summary: ATP7B c.3106G>A (p.Val1036Ile) results in a conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 248858 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (8.8e-05 vs 0.0054), allowing no conclusion about variant significance. c.3106G>A has been reported in the literature in the heterozygous state and in the presumed compound heterozygous state in at least two individuals affected with Wilson Disease (e.g. Simsek Papur_2013, Zarina_2017). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Simsek Papur_2015). The most pronounced variant effect results in intermediate effect on function as shown by a partial restoration of cell growth and non-restoration of copper transport activity in a yeast strain lacking the homologous CCC2 gene. The following publications have been ascertained in the context of this evaluation (PMID: 23333878, 19062534, 26004889, 28717664). ClinVar contains an entry for this variant (Variation ID: 553574). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2021

Krumina, 2008; Papur, 2015; Simsek Papur, 2013; Zarina, 2017 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 15, 2017

The ATP7B c.3106G>A;p.Val1036Ile variant has been described in at least two individuals with a clinical diagnosis of Wilson disease (Krumina 2008, Simsek Papur 2013). The variant is not listed in the ClinVar database, but is in the dbSNP variant database (rs761147984) with an allele frequency of 0.008319 percent (23/276486 alleles) in the Genome Aggregation Database. The amino acid at this position is moderately conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. However, at least one report shows this variant may be at least partially defective (Papur 2015). Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Krumina A et al. From clinical and biochemical to molecular genetic diagnosis of Wilson disease in Latvia. Genetika. 2008 Oct;44(10):1379-84. Papur OS et al. Functional characterization of new mutations in Wilson disease gene (ATP7B) using the yeast model. J Trace Elem Med Biol. 2015;31:33-6. Simsek Papur O et al. Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations. Eur J Med Genet. 2013 Apr;56(4):175-9. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

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

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.80

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

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.37

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

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

0.68

N;.;.;.;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.89

N;N;N;N;N;.;N

REVEL

Uncertain

0.59

Sift

Benign

0.11

T;T;T;T;T;.;T

Sift4G

Benign

0.21

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

Polyphen

0.25

B;D;B;B;B;B;B

Vest4

0.47

MVP

0.50

MPC

0.069

ClinPred

0.095

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.57

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