13-51942526-C-T

Position:

• chr13-51942526-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000053.4(ATP7B):​c.3272G>A​(p.Cys1091Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 7.86

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.3272G>A	p.Cys1091Tyr	missense_variant	15/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3272G>A	p.Cys1091Tyr	missense_variant	15/21	1	NM_000053.4	ENSP00000242839	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249554 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1091 of the ATP7B protein (p.Cys1091Tyr). This variant is present in population databases (rs778825095, gnomAD 0.003%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17587212). ClinVar contains an entry for this variant (Variation ID: 553303). 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. Experimental studies have shown that this missense change affects ATP7B function (PMID: 17587212). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 10, 2017

The ATP7B c.3272G>A; p.Cys1091Tyr variant is published in the medical literature in at least one individual with Wilson disease (Park 2007). Additionally, ARUP laboratories has detected this variant in an individual with Wilson disease who also carried a frameshift variant on the opposite chromosome. Another variant in the same codon, p.Cys1091Arg, is also published in the medical literature in an individual with suspected Wilson disease (Dong 2016). The p.Cys1091Tyr variant is not listed in the ClinVar database, but is listed in the dbSNP variant database (rs778825095), and in the Genomics Aggregation Database in 1/246220 alleles. The cysteine at codon 1091 is moderately conserved across species, occurs in the N domain important for ATP binding (Hercend 2011, Morgan 2004), and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. Hercend C et al. Elucidation of the ATP7B N-domain Mg2+-ATP coordination site and its allosteric regulation. PLoS One. 2011;6(10):e26245. Morgan CT et al. The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F. J Biol Chem. 2004 Aug 27;279(35):36363-71. Park S et al. Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. Hum Mutat. 2007 Nov;28(11):1108-13. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 08, 2017

Variant summary: The ATP7B c.3272G>A (p.Cys1091Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/246320 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in one Wilson disease patient in the literature as a compound heterozygous allele (Park_2007). This study also performed complementation assays that showed the variant reduced yeast growth compared to controls, suggesting normal function is impaired. Taken together, this variant is classified as VUS-possibly pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2021

The c.3272G>A (p.C1091Y) alteration is located in exon 15 (coding exon 15) of the ATP7B gene. This alteration results from a G to A substitution at nucleotide position 3272, causing the cysteine (C) at amino acid position 1091 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/249554) total alleles studied. The highest observed frequency was <0.01% (1/34524) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;.;.;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.6	D;D;D;D;D;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.011	D;D;D;D;D;.;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;B;D;P;D
Vest4		0.86
MutPred		0.82		Gain of phosphorylation at C1091 (P = 0.1094);.;.;.;.;.;.;
MVP		1.0
MPC		0.47
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.89
gMVP		0.92

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: rs778825095; hg19: chr13-52516662;