rs1412025509

Positions:

chr13-51944224-A-G

Variant summary

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

The NM_000053.4(ATP7B):c.3128T>C(p.Leu1043Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,002 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.43

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, 0.942

PP5

Variant 13-51944224-A-G is Pathogenic according to our data. Variant chr13-51944224-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550536.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.3128T>C	p.Leu1043Pro	missense_variant	14/21	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.3128T>C	p.Leu1043Pro	missense_variant	14/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

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

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727234

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

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

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 30, 2022	The ATP7B c.3128T>C; p.Leu1043Pro variant (rs1412025509) is reported in the literature in multiple individuals affected with Wilson disease, including several individuals that were homozygous or carried a second disease-causing variant (Curtis 1999, Guggilla 2015, Loudianos 1999, Nayagam 2022). The p.Leu1043Pro variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 1043 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.821). Consistent with these predictions, functional assays suggest the variant protein has reduced function, as it failed to complement growth on iron-limited media similar to wildtype ATP7B in a heterologous yeast assay (Luoma 2010). Based on available information, this variant is considered to be likely pathogenic. References: Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. PMID: 10502777. Guggilla SR et al. Spectrum of mutations in the ATP binding domain of ATP7B gene of Wilson Disease in a regional Indian cohort. Gene. 2015 Sep 10;569(1):83-7. PMID: 25982861. Loudianos G et al. Molecular characterization of wilson disease in the Sardinian population--evidence of a founder effect. Hum Mutat. 1999;14(4):294-303. PMID: 10502776. Luoma LM et al. Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. Hum Mutat. 2010 May;31(5):569-77. PMID: 20333758. Nayagam JS et al. ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants. Clin Gastroenterol Hepatol. 2022 Sep 9:S1542-3565(22)00837-0. PMID: 36096368. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1043 of the ATP7B protein (p.Leu1043Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ATP7B-related conditions and/or Wilson disease (PMID: 8931691, 23486543, 23518715, 24798599, 25982861, 36096368). This variant is also known as Leu1044Pro. ClinVar contains an entry for this variant (Variation ID: 550536). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2024	Published functional studies found this variant is associated with reduced ATP7B protein expression and is unable to rescue growth of a yeast strain deficient for ccc2 (the ATP7B otholog in yeast) (PMID: 20333758); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22692182, 18371106, 8931691, 25982861, 36096368, 23486543, 23518715, 10502777, 30230192, 18728530, 20333758) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 13, 2022	PP3, PP4, PM2, PM3, PS3_moderate, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Benign

0.88

DEOGEN2

Pathogenic

0.93

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

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

1.8

L;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.3

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

REVEL

Pathogenic

0.82

Sift

Benign

0.34

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

Sift4G

Benign

0.28

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

Polyphen

1.0

D;D;D;P;D;D;D

Vest4

0.88

MVP

0.98

MPC

0.47

ClinPred

0.97

GERP RS

5.4

Varity_R

0.88

gMVP

0.96

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