rs367956522

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000053.4(ATP7B):c.2731-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.77

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 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03069577 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.8, offset of -39, new splice context is: ggtgttttatttcttcatAGgtt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-51949798-T-C is Pathogenic according to our data. Variant chr13-51949798-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51949798-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.2731-2A>G		splice_acceptor_variant, intron_variant	Intron 11 of 20	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.2731-2A>G		splice_acceptor_variant, intron_variant	Intron 11 of 20	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

248258

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134902

show subpopulations

Gnomad AFR exome

AF:

0.0000652

Gnomad AMR exome

AF:

0.0000580

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:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461646

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000236

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:13

Jul 19, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ATP7B c.2731-2A>G variant located at a conserved intronic position, known to affect splicing with 5/5 splice prediction tools predicting a significant effect on splicing, which has been functionally supported (Shah_1997). This mutation produces 13 additional amino acids (VVISHGLGVLFSW) in the region between the transduction motif and the fifth Tm region. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/119818 (1/59909), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATP7B variant of 1/185. Multiple publications cite the variant in affected individuals including a homozygous individual, along with a reputable clinical laboratory citing the variant as "likely pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -

Dec 04, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the -2 position of intron 11 of the ATP7B gene. This variant has been reported in over ten individuals affected with Wilson disease (PMID: 9311736, 22677543, 23518715, 24094725; ClinVar: SCV000926218.1). In eight affected individuals, this variant has been determined to be homozygous or compound heterozygous with another pathogenic variant in the same gene, indicating that this variant contributes to Wilson disease in an autosomal recessive manner. RT-PCR analysis using cells derived from a homozygous individual revealed that this variant results in two aberrant transcripts, one with entire exon 12 (c.2731-2865; p.911-955) skipped and the other with in-frame insertion of 13 amino acids at the beginning of exon 12 due to the use of a cryptic acceptor site, 39-bp upstream from the native acceptor site (PMID: 9311736). This variant is expected to disrupt functionally important Actuator (phosphatase) domain (a.a. 786 - 917) and transmembrane M3 domain (a.a. 918 - 946). This variant has been identified in 7/279650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Aug 13, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2731-2A>G variant in ATP7B has been previously reported in individuals with Wilson disease, including at least 3 compound heterozygotes (Bost 2012 PMID: 22677543, Coffey 2013 PMID: 23518715, Mukherjee 2014 PMID: 24094725, Shah 1997 PMID: 9311736). In addition, RT-PCR analysis performed on lymphoblast culture from patients harboring the variant revealed an in-frame 39-bp insertion derived from a cryptic splice site (Shah 1997 PMID: 9311736). This variant has also been identified in 3/35320 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1_Strong, PM3_Strong, PM2_Supporting, PP4. -

Mar 20, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Feb 22, 2019

Laboratory for Population and Evolutionary Genetics, University of Puerto Rico at Mayaguez

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

dbSNP:rs367956522 in ATP7B has been reported segregating with Wilson's Disease in the UK with compound heterozygous in 3 cases (Coffey et al. 2013, PMID 23518715), and in the USA in both homozygous and compound heterozygous forms (Shah et al. 1997, PMID 9311736). In our unpublished study, all 4 individuals diagnosed with Wilson's Disease in southwestern Puerto Rico were homozygous for the minor allele. By contrast, none of the 214 healthy individuals tested were homozygous, In summary, dbSNP:rs367956522 is classified as pathogenic/likely pathogenic but meets our criteria to be classified as pathogenic. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 11 of the ATP7B gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with Wilson disease (PMID: 9311736, 23518715; internal data). ClinVar contains an entry for this variant (Variation ID: 188725). Studies have shown that disruption of this splice site results in skipping of exon 12 and insertion of additional nucleotides, but is expected to preserve the integrity of the reading-frame (PMID: 9311736). For these reasons, this variant has been classified as Pathogenic. -

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.2731-2A>G variant (rs367956522) is reported in the literature in multiple individuals affected with Wilson disease (Bost 2012, Coffey 2013, Mukherjee 2014, Shah 1997). This variant is reported by multiple laboratories in ClinVar (Variation ID: 188725), and is found in the general population with an overall allele frequency of 0.002% (7/279650 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice acceptor site of intron 11, and has been shown to alter splicing, causing an in-frame insertion of 39 nucleotides (Shah 1997), which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. 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 Jun;26(2-3):97-101. PMID: 22677543. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. PMID: 23518715. 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. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. PMID: 9311736. -

Sep 08, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This ATP7B canonical splice site variant (rs367956522) has been reported in the literature in association with Wilson disease. It is rare (<0.1%) in a large population dataset (gnomAD: 7/279650 total alleles; MAF 0.002503%; 0 homozygotes), and has an entry in ClinVar (Variation ID 188725). This variant destroys a canonical splice acceptor site, is predicted to cause abnormal gene splicing, and has supporting functional evidence. We consider this variant to be pathogenic. -

not provided

Pathogenic:2

Jan 19, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in association with Wilson disease (Bost et al., 2012; Shah et al., 1997; Mukherjee et al., 2014); Canonical splice site variant expected to result in aberrant splicing, with functional studies involving cDNA analysis demonstrating skipping of exon 12 (Shah et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23518715, 22677543, 9311736, 24094725) -

Aug 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_moderate, PM3, PS3, PVS1_strong -

Inborn genetic diseases

Pathogenic:1

May 17, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2731-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 12 in the ATP7B gene. This mutation was detected in a homozygous individual with Wilson disease who presented with neurological symptoms and liver disease. Functional studies showed that this mutation leads to abnormal splicing (Shah AB et al. Am. J. Hum. Genet., 1997 Aug;61:317-28). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

ATP7B-related disorder

Pathogenic:1

Feb 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATP7B c.2731-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with Wilson disease (Table 2, Shah et al. 1997. PubMed ID: 9311736; Table 1, Bost et al. 2012. PubMed ID: 22677543; Table 1, Mukherjee et al. 2013. PubMed ID: 24094725; pedigree 1, Coffey et al. 2013. PubMed ID: 23518715). RT-PCR from patient lymphoblast cells revealed this variant abolishes the exon 12 splice site and results in an in-frame inclusion of thirteen additional amino acids (Figure 1, Shah et al. 1997. PubMed ID: 9311736). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD and has an interpretation of pathogenic and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/188725/). Variants that disrupt the consensus splice acceptor site in ATP7B are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.83

Position offset: 37

DS_AL_spliceai

0.98

Position offset: -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