chr13-51942482-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

The NM_000053.4(ATP7B):c.3316G>A(p.Val1106Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000365 in 1,614,240 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:2

Conservation

PhyloP100: 7.86

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 4 ACMG points.

PM1

In a strand (size 6) in uniprot entity ATP7B_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-51942482-C-T is Pathogenic according to our data. Variant chr13-51942482-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495414.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=8, Uncertain_significance=2, Pathogenic=2}. Variant chr13-51942482-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.3499094). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.3316G>A	p.Val1106Ile	missense_variant	Exon 15 of 21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.3316G>A	p.Val1106Ile	missense_variant	Exon 15 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152228

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:

0.00192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

249580

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00156

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000756

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000474

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:10Uncertain:1

Oct 05, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.3316G>A (p.Val1106Ile) variant is a missense variant that has been widely reported in association with Wilson disease, primarily in individuals of Asian ancestry. Across a selection of the available literature, it was reported in a heterozygous state in at least 25 affected individuals (Wu et al. 2001; Liu et al. 2004; Li et al. 2011; Abuduxikuer et al. 2014; Mukherjee et al. 2014; Tu et al. 2015; Zong and Kong 2015; Dong et al. 2016; Hua et al. 2016; Poon et al. 2016; Yu et al. 2017). The presence and phase of additional variants were not clearly reported in many cases, but at least seven patients were compound heterozygous. In at least one case, the p.Val1106Ile variant was found in cis with a known pathogenic variant. These reports include a small case-control study, which found an OR of 10.44 (95% CI 1.36-79.97, corrected for multiple comparisons) for this variant (Dong et al. 2016). The p.Val1106Ile variant was identified in one out of 663 ethnically matched control individuals and is reported at a frequency of 0.001802 in the East Asian population of the Genome Aggregation Database. Functional studies in COS-7 cells suggested the variant, which is located in the ATP binding domain, does not impair protein localization, and studies in yeast indicated a minor impact on transport function (Park et al. 2007). However, lymphocytes from a compound heterozygous carrier showed ~45% of normal copper ATPase activity (Liu et al. 2004). Based on the collective evidence, the p.Val1106Ile variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Aug 22, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP7B c.3316G>A (p.Val1106Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 280988 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The frequency within the East Asian subpopulation is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (WD) (0.0017 vs. 0.0054), allowing no conclusion about variant significance. In the literature, this variant has been reported in a large number of WD patients, primarily of Asian (Chinese and Korean) origin, some patients are compound heterozygotes. This variant has also been reported to be found in the same allele with other pathogenic variants (Wu_2001, Dong_2016), providing evidence against pathogenicity. However, a small case-control study showed an odds ratio (OR) of ~10.5 (95%CI=1.36-79.9), suggesting that this variant may be a risk allele for Wilson disease (Dong_2016). Larger studies are required to confirm this finding. A functional assay showed no significant reduction in the variant's ability to rescue the delta-ccc2 yeast strain (i.e. the strain lacking the yeast gene ortholog), furthermore, confocal images showed that the variant protein localized to the same trans-Golgi network in COS-7 cells as the wild-type ATP7B (Park_2007). However, another study noted that the activity of Cu-ATPase in lymphocytes from a compound heterozygous patient was decreased by ~45% (Liu_2004). Furthermore, other missense variants affecting the same residue (p.V1106D, p.V1106L) have been reported to associate with Wilson disease and p.V1106D was reported as functionally deficient (PMID: 18203200). Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. One ClinVar submission cites the variant as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with isoleucine at codon 1106 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 does not impact protein localization in COS-7 cells (PMID: 17587212). In addition, this variant resulted in rescued function of ccc2 knockout yeast cells (PMID: 17587212). However, cells derived from an individual affected with Wilson disease and carrying this variant in the compound heterozygous state showed reduced activity of Cu-ATPase (PMID: 14966923). This variant has been reported in many individuals affected by Wilson disease (PMID: 11405812, 14966923, 21219664, 21796144, 24094725, 24475083, 25089800, 26782526, 26483271, 27022412, 27398169, 26650869, 27982432, 28212618, 28265897, 28515472, 29637721, 29930488, 30702195, 30884209), including a number of cases where this variant was in the compound heterozygous state (PMID: 28212618, 30702195, 30884209). However, several of these individuals carried three ATP7B variants, with at least one report that confirmed this variant was in cis with a known pathogenic variant (PMID: 11405812, 26483271, 27022412, 30884209). This variant has been identified in 36/280988 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. -

Jan 24, 2022

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PP4 -

Jun 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1106 of the ATP7B protein (p.Val1106Ile). This variant is present in population databases (rs541208827, gnomAD 0.2%). This missense change has been observed in individual(s) with Wilson disease (PMID: 14966923, 26483271, 28212618, 30702195). ClinVar contains an entry for this variant (Variation ID: 495414). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Dec 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.3316G>A; p.Val1106Ile variant (rs541208827) is reported in the literature in individuals affected with Wilson disease (Mukherjee 2014, Xiao 2021), including numerous compound heterozygous individuals (Huang 2022, Liu 2004, Qian 2019, Yu 2017, Zhang 2022). In addition, a small case-control study showed an odds ratio (OR) in favor of pathogenicity of approximately 10.5 (95%CI=1.36-79.9, Dong 2016). Functional analyses of the variant protein show no change from wild type in the variant's ability to rescue the delta-ccc2 yeast strain, and the variant protein localized to the same trans-Golgi network in COS-7 cells as wild-type ATP7B (Park 2007). However, lymphocytes from a compound heterozygous carrier showed approximately 45% of normal copper ATPase activity (Liu 2004). This variant is reported in ClinVar (Variation ID: 495414) and is found in the East Asian population with an allele frequency of 0.17% (33/19538 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.619). Based on available information, this variant is considered to be likely pathogenic. References: Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. PMID: 27022412. Huang C et al. Genetic studies discover novel coding and non-coding mutations in patients with Wilson's disease in China. J Clin Lab Anal. 2022 Jun;36(6):e24459. PMID: 35470480. Liu XQ et al. Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World J Gastroenterol. 2004 Feb 15;10(4):590-3. PMID: 14966923. Mukherjee S et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81. PMID: 24094725. Park S et al. Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. Hum Mutat. 2007 Nov;28(11):1108-13. PMID: 17587212. Qian Z et al. Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease. Mol Genet Genomic Med. 2019 May;7(5):e649. PMID: 30884209. Xiao Z et al. Molecular analysis of 53 Chinese families with Wilson's disease: Six novel mutations identified. Mol Genet Genomic Med. 2021 Sep;9(9):e1735. PMID: 34324271. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34. PMID: 28212618. Zhang S et al. Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China. Transl Neurodegener. 2022 Feb 28;11(1):13. PMID: 35220961. -

May 25, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Dec 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS3, PP4, PM2, PM3, PM5, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

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

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.35

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

MetaSVM

Pathogenic

0.92

MutationAssessor

Benign

0.79

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

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.81

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

REVEL

Uncertain

0.62

Sift

Benign

0.16

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

Sift4G

Benign

0.14

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

Polyphen

0.86

P;P;D;B;D;D;D

Vest4

0.70

MutPred

0.86

Gain of sheet (P = 0.0344);.;.;.;.;.;.;

MVP

0.85

MPC

0.33

ClinPred

0.25

GERP RS

4.8

Varity_R

0.30

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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