rs121907999

Positions:

• chr13-51974355-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000053.4(ATP7B):​c.865C>T​(p.Gln289Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,744 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q289Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ATP7B NM_000053.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: -0.0170

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-51974355-G-A is Pathogenic according to our data. Variant chr13-51974355-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51974355-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.865C>T	p.Gln289Ter	stop_gained	2/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.865C>T	p.Gln289Ter	stop_gained	2/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000282 AC: 7 AN: 248088 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134714

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000535

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461744 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 727162

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 16, 2019	Variant summary: ATP7B c.865C>T (p.Gln289X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 248088 control chromosomes (gnomAD). c.865C>T has been reported in the literature in several homozygous and compound heterozygous individuals affected with Wilson Disease (e.g. Waldenstrom_1996, Panagiotakaki_2004, Manolaki_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant changes 1 nucleotide in exon 2 of the ATP7B gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in many individuals affected with Wilson disease (PMID: 8938442, 9801873, 15523622, 15845031, 18403153, 19172127, 22677543, 23518715). In several of these individuals, this variant was reported in the compound heterozygous or homozygous state (PMID: 15523622, 15845031). This variant has been identified in 7/248088 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained c.865C>Tp.Gln289Ter variant in ATP7B gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Wilson disease Dedoussis et al., 2005. This variant is reported with the allele frequency of 0.003% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic Gromadzka et al., 2005. It has also been observed to segregate with disease in related individuals.For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Gln289X variant in ATP7B has been identified in several individuals with Wilson disease including at least 3 homozygotes and 4 compound heterozygotes (Bennet 2011, Bost 2012, Coffey 2013, Dedoussis 2005, Manolaki 2009, Mihaylova 2012, Panagiotakaki 2004, Waldenstrom 1996). It has been identified in 0.005% (6/112132) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is a low enough to be consistent with a recessive allele frequency. This nonsense variant leads to a premature termination codon at position 289, which is predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Gln289*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs121907999, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 15523622, 15845031, 18403153, 19172127). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3864). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	The ATP7B c.865C>T; p.Gln289Ter variant (rs121907999) is reported in the literature in homozygous and compound heterozygous individuals affected with Wilson disease (Couchonnal 2021, Manolaki 2009, Nayagam 2023, Panagiotakaki 2004, Waldenstrom 1996). This variant is also reported in ClinVar (Variation ID: 3864) and is found in the general population with an overall allele frequency of 0.003% (7/248088 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Couchonnal E et al. ATP7B variant spectrum in a French pediatric Wilson disease cohort. Eur J Med Genet. 2021 Oct;64(10):104305. PMID: 34400371. Manolaki N et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr. 2009 Jan;48(1):72-7. PMID: 19172127. Nayagam JS et al. ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants. Clin Gastroenterol Hepatol. 2023 May;21(5):1323-1329.e4. PMID: 36096368. Panagiotakaki E et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004 Dec 1;131(2):168-73. PMID: 15523622. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9. PMID: 8938442. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 15, 2017	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 26, 2019	PVS1, PS4, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2016	The Q289X nonsense variant in the ATP7B gene has been reported to be a common pathogenic variant in the Greek population and has been reported with severe, early-onset Wilson disease (Waldenström et al., 1996; Panagiotakaki et al., 2004; Manolaki et al., 2009; Behari et al., 2010). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.13	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.86
GERP RS		4.2

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: rs121907999; hg19: chr13-52548491;