13-51937570-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000053.4(ATP7B):āc.3809A>Gā(p.Asn1270Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,122 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00036 ( 0 hom., cov: 33)
Exomes š: 0.00012 ( 1 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.97
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 13-51937570-T-C is Pathogenic according to our data. Variant chr13-51937570-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3859.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=17}. Variant chr13-51937570-T-C is described in Lovd as [Pathogenic]. Variant chr13-51937570-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.3809A>G | p.Asn1270Ser | missense_variant | 18/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000361 AC: 55AN: 152236Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000216 AC: 54AN: 249580Hom.: 1 AF XY: 0.000244 AC XY: 33AN XY: 135404
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GnomAD4 exome AF: 0.000120 AC: 176AN: 1461886Hom.: 1 Cov.: 35 AF XY: 0.000131 AC XY: 95AN XY: 727246
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GnomAD4 genome 0.000361 AC: 55AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41AN XY: 74378
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:21Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:15Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
| Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 02, 2018 | Variant summary: ATP7B c.3809A>G (p.Asn1270Ser) results in a conservative amino acid change in the encoded protein sequence. 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 0.00015 in 120980 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00015 vs 0.0054), allowing no conclusion about variant significance. c.3809A>G has been reported in the literature in numerous individuals affected with Wilson Disease as both a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence on the variant and showed that copper uptake and transport are both defective (Huster_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jun 14, 2023 | A homozygous missense variant in exon 18 of the ATP7B gene that results in the amino acid substitution of Serine for Asparagine at codon 1270 (p.Asn1270Ser) was detected. The p.Asn1270Ser variant has not been reported in the 1000 genomes databases and has a minor allele frequency of 0.04%, 0.02% and 0.03% in the gnomAD (v3.1), gnomdAD (v2) and topmed databases respectively. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1270 of the ATP7B protein (p.Asn1270Ser). This variant is present in population databases (rs121907990, gnomAD 0.08%). This missense change has been observed in individuals with Wilson disease (PMID: 20485189, 26269689, 27398169). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3859). 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: 9654149, 22240481). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 22, 2022 | The ATP7B c.3809A>G; p.Asn1270Ser variant (rs121907990) is reported in the literature in numerous individuals affected with Wilson disease (Abuduxikuer 2015, Barada 2010, Daneshjoo 2018, Guggilla 2015, Hua 2016, Tanzi 1993, Todorov 2005). This variant has been reported to cosegregate with disease in families, both in the homozygous state (Barada 2010, Tanzi 1993) and in trans to another pathogenic variant (Daneshjoo 2018). The asparagine at codon 1270 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.896). Biochemical analyses indicate this variant has severely reduced copper transport activity (Huster 2012), and it fails to rescue growth defects of mutant yeast to the extent of wildtype protein (Iida 1998). Additionally, other variants at this codon (p.Asn1270Asp, p.Asn1270Ile) have been reported in Wilson disease patients (Nemeth 2016, Tuan Pham 2017). The p.Asn1270Ser variant is reported in ClinVar (Variation ID: 3859), and is found in the general population with an overall allele frequency of 0.020% (55/280972 alleles, including a single homozygote) in the Genome Aggregation Database. Based on available information, the p.Asn1270Ser variant is considered to be pathogenic. References: Abuduxikuer K et al. Wilson disease with hepatic presentation in an eight-month-old boy. World J Gastroenterol. 2015 Aug 7;21(29):8981-4. PMID: 26269689. Barada K et al. Homozygous mutations in the conserved ATP hinge region of the Wilson disease gene: association with liver disease. J Clin Gastroenterol. 2010 Jul;44(6):432-9. PMID: 20485189. Daneshjoo O and Garshasbi M. Novel compound heterozygote mutations in the ATP7B gene in an Iranian family with Wilson disease: a case report. J Med Case Rep. 2018 Mar 15;12(1):68. PMID: 29540233. Guggilla SR et al. Spectrum of mutations in the ATP binding domain of ATP7B gene of Wilson Disease in a regional Indian cohort. Gene. 2015 Sep 10;569(1):83-7. PMID: 25982861. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. PMID: 27398169. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. PMID: 22240481. Iida M et al. Analysis of functional domains of Wilson disease protein (ATP7B) in Saccharomyces cerevisiae. FEBS Lett. 1998 May 29;428(3):281-5. PMID: 9654149. Nemeth D et al. Clinical Use of Next-Generation Sequencing in the Diagnosis of Wilson's Disease. Gastroenterol Res Pract. 2016;2016:4548039. PMID: 26819605. Tanzi RE et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993 Dec;5(4):344-50. PMID: 8298641. Todorov T et al. Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. Clin Genet. 2005 Nov;68(5):474-6. PMID: 16207219. Tuan Pham LA et al. Genetic analysis of 55 northern Vietnamese patients with Wilson disease: seven novel mutations in ATP7B. J Genet. 2017 Dec;96(6):933-939. PMID: 29321352. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2024 | This missense variant replaces asparagine with serine at codon 1270 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant alters a residue in the phosphorylation domain of the ATP7B protein (a.a. 1004 - 1031 and a.a. 1197 - 1306), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). Functional studies in Chinese hamster ovary cells have shown the mutant protein to exhibit significantly reduced copper uptake and transport, and increased phosphorylation relative to wild type (PMID: 22240481). In a separate study, this variant was unable to rescue function in a knockout ccc2 yeast model (PMID: 9654149). This variant has been reported in many individuals affected with Wilson disease (PMID: 7626145, 9311736, 9452121, 10790207, 12544487, 17587212, 18483695, 19419418, 16696937, 23235335, 23518715, 25982861, 26269689, 27398169). In a number of these individuals, this variant was confirmed to be in the homozygous state or in the compound heterozygous state with a second pathogenic variant (PMID: 10790207, 12544487, 18483695, 23518715). This variant has been identified in 55/280972 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 11, 2020 | The p.Asn1270Ser variant in ATP7B has been identified in >50 probands across multiple ethnic groups with Wilson disease, including at least 4 homozygotes and >15 compound heterozygotes, and has segregated in at least 4 affected siblings (Abuduxikuer 2015, Barada2010, Bost 2012, Chen 2019, Coffey 2013, Daneshjoo 2018, Deguti 2004, Dong 2016, Guggilla 2015, Hua 2016, Kuppala 2009, Li 2013, Okada 2000, Shah 1997, Wan 2010, Yoo 2002, Zali 2011). This variant has also been identified in 0.08% (30/35376) of Latino chromosomes, including 1 homozygote by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency given an estimated prevalence of 1/30000 for Wilson disease. In vitro functional studies suggest that the variant may impact protein function (Huster 2012, Lida 1998), and computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PP3, PP4, PS3_Supporting. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 03, 2020 | NM_000053.3(ATP7B):c.3809A>G(N1270S) is classified as pathogenic in the context of Wilson Disease. Sources cited for classification include the following: PMID 23518715, 12544487, 22240481, 10790207, 9452121, 9829905, 19419418, 9311736, 7626145 and 9654149. Classification of NM_000053.3(ATP7B):c.3809A>G(N1270S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 06, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 09, 2023 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | ATP7B: PM2, PM3, PM5, PP1, PP4, PS3:Supporting, PS4:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2022 | Published functional studies indicate that this variant leads to hyperphosphorylation and affects copper transport, supporting a damaging effect (Iida et al., 1998; Huster et al., 2012); 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, 20485189, 22240481, 9654149, 29540233, 8298641, 32154060, 30655162, 23518715, 30275481, 25637381, 22692182, 25982861, 26269689, 27398169, 10194254, 9829905, 19419418, 7626145, 9452121, 12544487, 10790207, 9311736, 30558096, 31708252, 34324271, 31589614, 34426522, 34240825, 34470610, Huong2022[article], 35222532, 33879678, Rosa2022[article], 34002136, 35395623) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 11, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 17, 2024 | PP3, PP4, PP5, PM2_moderate, PS3, PS4_moderate - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2017 | The p.N1270S pathogenic mutation (also known as c.3809A>G), located in coding exon 18 of the ATP7B gene, results from an A to G substitution at nucleotide position 3809. The asparagine at codon 1270 is replaced by serine, an amino acid with highly similar properties. This mutation has been identified in multiple individuals with Wilson disease, including several homozygous individuals (Yoo HW. Genet. Med. 2002;4:43S-48S; Deguti MM et al. Hum. Mutat., 2004 Apr;23:398; Barada K et al. J. Clin. Gastroenterol., 2010 Jul;44:432-9). When expressed in Sf9 cells, this mutation demonstrated impaired chloride transport and hyperphosphorylation (Huster D et al. Gastroenterology, 2012 Apr;142:947-956.e5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
ATP7B-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 03, 2023 | The ATP7B c.3809A>G variant is predicted to result in the amino acid substitution p.Asn1270Ser. This variant has been repeatedly documented as causative for Wilson disease (Tanzi et al. 1993. PubMed ID: 8298641; Yoo et al. 2002. PubMed ID: 12544487; Zhang et al. 2013. PubMed ID: 23235335). Functional studies suggest that this variant alters normal protein function (Table S1, Schushan et al. 2012. PubMed ID: 22692182). In summary, we interpret this variant as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at