rs587783306

chr13-51949661-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.2865+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000372 in 1,613,670 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.13

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.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.030468395 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 13-51949661-C-T is Pathogenic according to our data. Variant chr13-51949661-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 157942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51949661-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2865+1G>A		splice_donor_variant		ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2865+1G>A		splice_donor_variant		1	NM_000053.4	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249060

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461460

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This variant causes a G to A nucleotide substitution at the +1 position of intron 12 of the ATP7B gene. In the literature, this variant has also been reported as IVS12+1G>A. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant is likely to cause in-frame skipping of exon 12. Multiple pathogenic missense variants have been reported in this exon (ClinVar), indicating the functional and clinical importance of the region may be affected by this variant. This variant has been observed in 11 individuals affected with autosomal recessive Wilson disease (15967699, 22677543, 23551039, PMID: Kuchar, E et al 2008, 30120852, 33640437, 34400371) of which two are compound heterozygous and five are homozygous for this variant, indicating that this variant contributes to disease. This variant has been identified in 4/249060 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 16, 2021	NM_000053.3(ATP7B):c.2865+1G>A is a canonical splice variant classified as pathogenic in the context of Wilson disease. c.2865+1G>A has been observed in cases with relevant disease (PMID: 23551039, 15967699, 30120852, 33640437, 22677543). Functional assessments of this variant are not available in the literature. c.2865+1G>A has been observed in population frequency databases (gnomAD: SAS <0.003%). In summary, NM_000053.3(ATP7B):c.2865+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 03, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 157942). This variant is also known as IVS12+1G>A. Disruption of this splice site has been observed in individual(s) with clinical features of Wilson disease (PMID: 15967699, 23551039, 30120852). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs587783306, gnomAD 0.003%). This sequence change affects a donor splice site in intron 12 of the ATP7B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.43

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

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

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.95

Position offset: 1

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