rs201061621

chr13-51946423-G-Achr13-51946423-G-Cchr13-51946423-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000053.4(ATP7B):c.2921C>T(p.Thr974Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T974T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:14 O:1
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2921C>T	p.Thr974Met	missense_variant	13/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2921C>T	p.Thr974Met	missense_variant	13/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

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: 0.000426

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000144 AC: 36 AN: 249450 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135348

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 264 AN XY: 727222

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000467

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74384

Gnomad4 AFR AF: 0.000289

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: 0.000426

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000321 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000494 AC: 2

ESP6500EA AF: 0.000595 AC: 5

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Uncertain:8 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces threonine with methionine at codon 974 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: 18373411, 27935710, 30097039). In one of these individuals, this variant was reported in the compound heterozygous state (PMID: 27935710). This variant has been identified in 46/280856 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 16, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2022	The ATP7B c.2921C>T; p.Thr974Met variant (rs201061621) has been described in an individual with a clinical diagnosis of Wilson disease (Davies 2008). The variant is reported in the ClinVar (Variation ID: 289465) and is listed in the general population with an overall allele frequency of 0.016% (46/280856 alleles) in the Genome Aggregation Database. The threonine at codon 974 is moderately conserved, occurs in the ATPase domain, and computational analyses predict that this variant is deleterious (REVEL: 0.746). Additionally, other variants in threonines in this region (p.Thr935Met, p.Thr977Met) are considered pathogenic. However, given the lack of clinical and functional data, the significance of the p.Thr974Met variant is uncertain at this time. References: Davies LP et al. New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genet Test. 2008 Mar;12(1):139-45. PMID: 18373411. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 21, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 974 of the ATP7B protein (p.Thr974Met). This variant is present in population databases (rs201061621, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. ClinVar contains an entry for this variant (Variation ID: 289465). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 03, 2017	- -

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	Reported previously in an individual with a reported diagnosis of Wilson disease; however, further phenotypic information was not provided, and it is unclear whether or not this individual also harbored a second ATP7B variant (Davies et al., 2008); Reported in an individual with alcoholic liver cirrhosis whose biochemistry did not support a diagnosis of Wilson disease (Jung et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 30097039, 18373411, 27935710, 22692182) -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 19, 2022	PP3 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 18, 2024

Variant summary: AATP7B c.2921C>T (p.Thr974Met) results in a non-conservative amino acid change located in the transmembrane 6 region, could affect protein conformation, as other variants (DVs) in this domain have been shown to do, or disrupt the transport of copper across the lipid bilayer. However, there are currently no studies to support such predictions. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 249500 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00014 vs 0.0054), allowing no conclusion about variant significance. c.2921C>T has been reported in the literature in individuals affected with Wilson Disease (examples: Davies_2008, Jung_2017). These data do not allow any conclusion about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 30097039, 18373411, 27935710, 23235335, 20465995, 31449670, 22692182, 31059521, 24253677, 31751128). ClinVar contains an entry for this variant (Variation ID: 289465). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2021

Identified in one patient with Wilson disease; however, no second ATP7B variant was reported (Davies, 2008)_x000D_ _x000D_ Studies of evolutionary conservation and structure were inconclusive regarding the effect of this alteration on protein function (Schushan, 2012) 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	Benign	0.13
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;D;.;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.36	N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.5	N;N;N;D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.020	D;D;T;T;D;.
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		1.0	D;D;D;P;P;P
Vest4		0.80
MVP		0.98
MPC		0.38
ClinPred		0.21	T
GERP RS		5.2
Varity_R		0.32
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201061621; hg19: chr13-52520559; COSMIC: COSV105028332;