rs200290721

chr13-51946366-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000053.4(ATP7B):c.2978C>T(p.Thr993Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,613,282 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). Synonymous variant affecting the same amino acid position (i.e. T993T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:9
• Conservation: PhyloP100: 9.94

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 9 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 13-51946366-G-A is Pathogenic according to our data. Variant chr13-51946366-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554771.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=8, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2978C>T	p.Thr993Met	missense_variant	13/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2978C>T	p.Thr993Met	missense_variant	13/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000722 AC: 11 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000846 AC: 21 AN: 248286 Hom.: 0 AF XY: 0.0000964 AC XY: 13 AN XY: 134852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461030 Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 83 AN XY: 726752

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74394

Gnomad4 AFR AF: 0.0000241

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000976 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Pathogenic:1 Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 13, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2022	The ATP7B c.2978C>T; p.Thr993Met variant (rs200290721) is reported in the literature in two individuals affected with Wilson disease, in one case on the opposite chromosome to a second pathogenic variant (Lepori 2007, Loudianos 2013). This variant is reported in ClinVar (Variation ID: 554771) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 993 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.865). Due to limited information, the clinical significance of the p.Thr993Met variant is uncertain at this time. References: Lepori et al. Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin. Genet Test. 2007 Fall;11(3):328-32. PMID: 17949296. Loudianos G et al. Wilson's disease in two consecutive generations: the detection of three mutated alleles in the ATP7B gene in two Sardinian families. Dig Liver Dis. 2013 Apr;45(4):342-5. PMID: 23219664. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces threonine with methionine at codon 993 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease (PMID: 17949296, 23219664). This variant has been identified in 24/279690 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 993 of the ATP7B protein (p.Thr993Met). This variant is present in population databases (rs200290721, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17949296, 23219664). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as T993W. ClinVar contains an entry for this variant (Variation ID: 554771). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in two unrelated patients with bipolar disorder and schizophrenia (Sriretnakumar et al., 2019); This variant is associated with the following publications: (PMID: 30556376, 22692182, 23219664, 17949296, 18728530) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 26, 2022	PP3, PP4, PM2, PM3 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 27, 2022

Variant summary: ATP7B c.2978C>T (p.Thr993Met) 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 allele was found at a frequency of 8.5e-05 in 248286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (8.5e-05 vs 0.0054), allowing no conclusion about variant significance. c.2978C>T has been reported in the literature as a non-informative genotype (second allele/genotype not clearly specified) reported among Wilson Disease chromosomes (example, Lepori_2007, cited in Zappu_2008, Gialluisi_2013) and as a compound heterozygous genotype in at-least one individual affected with clinically and biochemically consistent diagnosis of Wilson Disease (example, Loudianos_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=1; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2021

The c.2978C>T (p.T993M) alteration is located in exon 13 (coding exon 13) of the ATP7B gene. This alteration results from a C to T substitution at nucleotide position 2978, causing the threonine (T) at amino acid position 993 to be replaced by a methionine (M). 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.0	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;D;B;P;D
Vest4		0.94
MVP		0.95
MPC		0.38
ClinPred		0.73	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
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: rs200290721; hg19: chr13-52520502;