rs786204552

Positions:

• chr13-51935629-G-A
• chr13-51935629-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.4088C>T​(p.Ser1363Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1363Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a transmembrane_region Helical (size 19) in uniprot entity ATP7B_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51935629-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 13-51935629-G-A is Pathogenic according to our data. Variant chr13-51935629-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51935629-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.4088C>T	p.Ser1363Phe	missense_variant	20/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.4088C>T	p.Ser1363Phe	missense_variant	20/21	1	NM_000053.4	ENSP00000242839	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP7B function (PMID: 19937698). 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. ClinVar contains an entry for this variant (Variation ID: 188908). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 21610751, 24094725). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1363 of the ATP7B protein (p.Ser1363Phe). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2021	Variant summary: ATP7B c.4088C>T (p.Ser1363Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246976 control chromosomes (gnomAD). c.4088C>T (p.Ser1363Phe) has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Wilson Disease (e.g. Loudianos_1999, Moller_2011, Mukherjee_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (e.g. van den Berghe_2009). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 23, 2022

PP3, PP4, PM2, PM3_strong, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;.;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.97
MutPred		0.92		Loss of disorder (P = 0.0027);.;.;.;.;.;.;
MVP		0.99
MPC		0.35
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.75
gMVP		0.85

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

Other links and lift over

dbSNP: rs776848753; hg19: chr13-52509765;