rs749472361

Positions:

• chr13-51937484-G-A
• chr13-51937484-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.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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1299P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.95

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain 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 chr13-51937483-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2570866.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	UniProt
ATP7B	NM_000053.4	c.3895C>T	p.Leu1299Phe	missense_variant	18/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3895C>T	p.Leu1299Phe	missense_variant	18/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000361 AC: 9 AN: 249420 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135332

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: 23 AN: 1461720 Hom.: 0 Cov.: 35 AF XY: 0.0000206 AC XY: 15 AN XY: 727152

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.: 33

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000495 AC: 6

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
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	D
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

Other links and lift over

dbSNP: rs749472361; hg19: chr13-52511620;