rs755554442

chr13-51941186-G-Achr13-51941186-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):c.3451C>T(p.Arg1151Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,994 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1151H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.47

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51941185-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495415.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 13-51941186-G-A is Pathogenic according to our data. Variant chr13-51941186-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941186-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.3451C>T	p.Arg1151Cys	missense_variant	16/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3451C>T	p.Arg1151Cys	missense_variant	16/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000561 AC: 14 AN: 249588 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461890 Hom.: 1 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74274

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:10 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Likely pathogenic and reported on 04-18-2019 by Lab or GTR ID 507240. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with cysteine at codon 1151 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant alters a conserved arginine residue in the ATP nucleotide-binding domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). Experimental studies have shown that this variant results in abnormal function in yeast complementation and growth assays (PMID: 21645214). This variant has been reported in numerous individuals affected with Wilson disease (PMID: 17949296, 21645214, 22484412, 23235335, 23333878, 26215059, 27398169, 27022412, 34428338, 34620762; DOI:10.46531/sinapse/AO/210033/2021). In at least one of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene, indicating that this variant contributes to Wilson disease in an autosomal recessive manner (PMID: 23333878, 26215059). This variant has been identified in 14/249588 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 05, 2022	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 20, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 24, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 06, 2022	This variant was identified with NM_000053.4:c.1285+5G>T, phase is unknown. Both variants were reported as secondary findings in a patient without Wilson associated symptoms Criteria applied: PM3_STR, PS3_MOD, PM5, PM2_SUP, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Arg1151Cys variant in ATP7B has been reported in more than 5 individuals with Wilson disease (at least 3 in the compound heterozygous state)(Lepori 2007 PMID: 17949296, Lee 2011 PMID:21645214, Papur 2013 PMID: 23333878, Hua 2016 PMID: 27398169, Dong 2016 PMID: 27022412). This variant has also been reported in ClinVar (Variation ID: 188839). It has also been identified in 1/4822 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Lee 2011 PMID: 21645214). Other variants involving this codon (including the likely pathogenic p.Arg1151His) have been identified in individuals with Wilson disease. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM2_supporting, PP3, PM5, PS3_Supporting, PM3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1151 of the ATP7B protein (p.Arg1151Cys). This variant is present in population databases (rs755554442, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17949296, 21645214, 23333878, 27398169). ClinVar contains an entry for this variant (Variation ID: 188839). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 21645214). This variant disrupts the p.Arg1151 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10544227, 15205462, 30655162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 16, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2023	Published functional studies demonstrate a damaging effect (Lee et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24253677, 22692182, 17949296, 26215059, 22484412, 21645214, 23333878, 32231684, 30275481, 23089210, 15147237, 27022412, 23235335, 34470610, 34620762, Rosa[article]2021) -

ATP7B-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2023

The ATP7B c.3451C>T variant is predicted to result in the amino acid substitution p.Arg1151Cys. This variant was reported in multiple individuals with Wilson disease (Lepori et al. 2007. PubMed ID: 17949296, Lee et al. 2011. PubMed ID: 21645214, Hua et al. 2016. PubMed ID: 27398169). It is unclear based on the literature if these variants were seen in the homozygous or compound heterozygous state. However, it was reported with a second pathogenic variant in one patient with clinical and biochemical features consistent with Wilson disease (Simsek Papur et al. 2013. PubMed ID: 23333878). In vitro functional characterization suggests that this variant is deleterious (Lee et al. 2011. PubMed ID: 21645214). Of note, two additional missense variants affecting this residue have been reported in association with Wilson disease with unclear evidence of pathogenicity (p.Arg1151His and p.Arg1151Gly; Morgan et al. 2004. PubMed ID: 15205462, Loudianos et al. 1999. PubMed ID: 10544227, Dong et al. 2016. PubMed ID: 27022412). This variant is located in exon 16, where a large number of ATP7B variants have been associated with disease (Li. 2021. PubMed ID: 34470610). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52515322-G-A). Of note, this variant was also detected in a patient who carried two additional likely pathogenic/pathogenic variants in this gene. Overall, the collective evidence suggests that this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D;.;.;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.86
MutPred		0.89		Loss of MoRF binding (P = 0.0101);.;.;.;.;.;.;
MVP		0.99
MPC		0.43
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs755554442; hg19: chr13-52515322; COSMIC: COSV54438170; COSMIC: COSV54438170;