rs193922109

chr13-51937342-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.3955C>T(p.Arg1319Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,614,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1319R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: ATP7B NM_000053.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: -0.762

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 13-51937342-G-A is Pathogenic according to our data. Variant chr13-51937342-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 35728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51937342-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.3955C>T	p.Arg1319Ter	stop_gained	19/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3955C>T	p.Arg1319Ter	stop_gained	19/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000761 AC: 19 AN: 249580 Hom.: 0 AF XY: 0.0000739 AC XY: 10 AN XY: 135408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 214 AN: 1461890 Hom.: 1 Cov.: 35 AF XY: 0.000165 AC XY: 120 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74296

Gnomad4 AFR AF: 0.0000725

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.0000413 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Arg1319X variant in ATP7B has been previously reported in >15 probands with Wilson disease, including at least 10 compound heterozygous and three homozygous individuals, and has segregated in 4 affected family members (Coffey 2013, Abdelghaffar 2008, Deguti 2004). This variant has been identified in 0.01% (14/128714) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1319, 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_VeryStrong, PP1_Moderate, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2021	The ATP7B c.3955C>T; p.Arg1319Ter variant (rs193922109) is described in the medical literature as homozygous or in combination with other pathogenic variants in individuals with Wilson disease (Abdelghaffar 2008, Balashova 2020, Deguti 2004, Margarit 2005, Waldenstrom 1996). This variant is found in the general population with an overall allele frequency of 0.007% (20/280972 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Abdelghaffar TY et al. Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. J Hum Genet. 2008;53(8):681. Balashova MS et al. The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. J Trace Elem Med Biol. 2020 May;59:126420. PMID: 31708252. Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This variant changes 1 nucleotide in exon 19 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 observed in the compound heterozygous state or homozygous state in many individuals affected with autosomal recessive Wilson disease (PMID: 7626145, 8533760, 8938442, 9311736, 10544227, 11472373,15024742, 15952988, 16545904, 17897870, 18034201, 18371106, 18483695, 19118915, 20967755, 21682854, 21796144, 23333878, 23518715, 27022412, 31708252), indicating that this variant contributes to disease. This variant has been identified in 20/280972 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, criteria provided, single submitter	research	Institute for Genomic Medicine, Nationwide Children's Hospital	Apr 20, 2021	The p.Arg1319* nonsense variant in ATP7B is a well-established pathogenic variant and has been reported in numerous patients to date. It is present at very low frequency in the gnomAD database (MAF<0.0001) and is predicted to truncate a significant portion of the protein. Multiple reputable laboratories have recently reported it as pathogenic. We interpret the variant as pathogenic. We identified this variant in a proband with clinical Wilson's disease; it was in compound-heterozygous state with a synonymous change (p.Leu1015=) shown to cause exon skipping by research RNA-seq. In that same experiment, we observed that the p.Arg1319* variant was present in <25% of RNA reads, suggesting that variant transcripts are subject to nonsense-mediated decay. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Arg1319*) 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 (rs193922109, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 893844, 7626145, 15024742, 15952988, 18483695, 21682854, 21796144, 23518715, 27022412). ClinVar contains an entry for this variant (Variation ID: 35728). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 14, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 29, 2022	PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2021	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22774841, 8938442, 11472373, 7626145, 8533760, 10544227, 19118915, 18483695, 25497208, 34240825, 25525159, 18371106, 31708252, 34324271, 23333878, 27022412, 23518715, 21796144, 21682854, 20967755, 18034201, 16283883, 31589614, 30556376, 30291343, 32513368) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2015

The p.R1319* pathogenic mutation (also known as c.3955C>T and p.R1319X), located in coding exon 19 of the ATP7B gene, results from a C to T substitution at nucleotide position 3955. This changes the amino acid from an arginine to a stop codon within coding exon 19. This mutation was identified in the homozygous state in four patients with a clinical diagnosis of Wilson disease and who exhibited lower serum copper levels (Nicastro E et al. J Hepatol. 2009;50(3):555-61). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	35
Dann	Uncertain	0.98
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.079	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.95
GERP RS		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs193922109; hg19: chr13-52511478; COSMIC: COSV54442352; COSMIC: COSV54442352;