rs749472361

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.3895C>T(p.Leu1299Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.95

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 13-51937484-G-A is Pathogenic according to our data. Variant chr13-51937484-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.3895C>T	p.Leu1299Phe	missense_variant	18/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.3895C>T	p.Leu1299Phe	missense_variant	18/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249420

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135332

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:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727152

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:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000896

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 22, 2022	Variant summary: ATP7B c.3895C>T (p.Leu1299Phe) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of 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 3.6e-05 in 249420 control chromosomes (gnomAD). c.3895C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Wilson Disease (examples: Mukherjee_2014 and Aggarwal_2013). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1299 of the ATP7B protein (p.Leu1299Phe). This variant is present in population databases (rs749472361, gnomAD 0.03%). This missense change has been observed in individual(s) with Kayser-Fleischer rings and plasma ceruloplasmin <= 20 mg/dL, findings that are highly specific for Wilson disease (PMID: 24094725). ClinVar contains an entry for this variant (Variation ID: 189149). 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 expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.L1299F in ATP7B (NM_000053.4) causes the same amino acid change as a previously established pathogenic variant. The p.L1299F variant is observed in 9/30,602 (0.0294%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.L1299F missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.3895 in ATP7B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 22, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 21, 2021	- -

ATP7B-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2024

The ATP7B c.3895C>T variant is predicted to result in the amino acid substitution p.Leu1299Phe. This variant has been reported in both the homozygous and stated compound heterozygous state in individuals, particularly of Indian descent, with Wilson disease (Santhosh et al. 2006. PubMed ID: 17264425; Mukherjee et al. 2013. PubMed ID: 24094725; Aggarwal et al. 2013. PubMed ID: 23551039; Nayagam et al. 2022. PubMed ID: 36096368). This variant is reported in 0.029% of alleles in individuals of South Asian descent in gnomAD and has been consistently interpreted as pathogenic and likely pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/189149/). Additionally, a different missense change impacting the same amino acid (c.3896T>G, p.Leu1299Arg) was observed in an individual from a Wilson disease cohort study (Table 2, Dong et al. 2016. PubMed ID: 27022412). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

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

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

M;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.6

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

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0090

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.97

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

Vest4

0.91

MutPred

0.91

Gain of catalytic residue at L1299 (P = 0.0101);.;.;.;.;.;.;

MVP

1.0

MPC

0.39

ClinPred

0.87

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.91

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