rs201738967
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3PP5
The NM_000053.4(ATP7B):āc.122A>Gā(p.Asn41Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000614 in 1,614,114 control chromosomes in the GnomAD database, including 2 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 0.00024 ( 0 hom., cov: 33)
Exomes š: 0.00065 ( 2 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 6.72
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
In a mutagenesis_site Altered copper-induced relocalization. (size 0) in uniprot entity ATP7B_HUMAN
PP3
MetaRNN computational evidence supports a deleterious effect, 0.8
PP5
Variant 13-51975098-T-C is Pathogenic according to our data. Variant chr13-51975098-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157928.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=6, Likely_pathogenic=14}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.122A>G | p.Asn41Ser | missense_variant | 2/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATP7B | ENST00000242839.10 | c.122A>G | p.Asn41Ser | missense_variant | 2/21 | 1 | NM_000053.4 | ENSP00000242839.5 |
Frequencies
GnomAD3 genomes 0.000237 AC: 36AN: 152220Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000241 AC: 60AN: 249446Hom.: 0 AF XY: 0.000281 AC XY: 38AN XY: 135330
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GnomAD4 exome AF: 0.000653 AC: 955AN: 1461894Hom.: 2 Cov.: 33 AF XY: 0.000631 AC XY: 459AN XY: 727248
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GnomAD4 genome 0.000237 AC: 36AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74354
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:22Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:14Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jul 07, 2023 | This sequence change in ATP7B is predicted to replace asparagine with serine at codon 41, p.(Asn41Ser). The asparagine residue is highly conserved (100 vertebrates, UCSC), and is located in the NXXY motif, a region that is shown to be critical for ATP7B protein transport (PMID: 19033537). There is a small physicochemical difference between asparagine and serine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.047% (61/128,586 alleles) in the European (non-Finnish) population. Computational evidence is uninformative for the missense substitution (REVEL = 0.569). This variant has been detected in at least four individuals with a clinical diagnosis of Wilson disease. These individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and were confirmed in trans (PMID:15024742, 23518715, 22820477, 33640437). Heterozygous variants in ATP7B have been reported in individuals with late-onset Parkinson's Disease and Wilson Disease (PMID: 31426520, 33972609). An in vitro functional assay using WIF-B cells and mutagenesis showed a complete disruption in protein trafficking in the basolateral membrane indicating that this variant impacts protein function, however, the reason for copper accumulation is still unknown (PMID: 19033537). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM1, PM2_Supporting, PS3_Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | This missense variant replaces asparagine with serine at codon 41 of the ATP7B protein. This variant is located in the p.Phe37_Glu45 sequence that is thought to be an essential apical targeting determinant for ATP7B in elevated copper condition and participate in the post-trans-Golgi network retention of the protein under low-copper condition (PMID: 19033537). Functional studies have shown that this variant results in reduced protein stability and defective copper-induced trafficking of ATP7B protein (PMID: 19033537, 37660282, 38032054). This variant has been observed in many individuals affected with autosomal recessive Wilson disease with at least four individuals confirmed to carry this variant in compound heterozygosity with a second pathogenic variant (PMID: 15024742, 22677543, 22820477, 23518715, 32770663, 33640437, 36096368; DOI: 10.21203/rs.3.rs-2858430/v1, 10.12996/gmj.2023.3795; ClinVar Accession: SCV000626829.6). This variant has been identified in 68/280840 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 | Fulgent Genetics, Fulgent Genetics | Jun 01, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 06, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 21, 2022 | Variant summary: ATP7B c.122A>G (p.Asn41Ser) 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 0.00024 in 249566 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00024 vs 0.0054), allowing no conclusion about variant significance. c.122A>G has been reported in the literature in individuals affected with Wilson Disease (e.g. Deguti_2004, Ben-Rebah_2012, Bost_2012,Coffey_2013, Woimant_2020 and Collins_2021). These data indicate that the variant is likely to be associated with disease. The variant has also been found, however, in compound heterozygosity with another pathogenic variant (p.Arg1319X) in a 43-year old individual who was asymptomatic (Brunet_2012). At least one publication reports experimental evidence evaluating an impact on protein function, and suggests that the variant impairs copper-sensitive ATP7B protein targeting and retention (Braiterman_2009). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=4) and likely pathogenic (n=8). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 41 of the ATP7B protein (p.Asn41Ser). This variant is present in population databases (rs201738967, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical and biochemical features of Wilson disease (PMID: 15024742, 22677543, 23518715; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 157928). 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 95%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 19033537, 21454443). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 24, 2020 | The ATP7B c.122A>G; p.Asn41Ser variant (rs201738967) has been described in at least 3 individuals affected with Wilson disease and two of these individuals carry a second pathogenic ATP7B variant (Bost 2012, Coffey 2013, Deguti 2004). It is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 157928) and observed in the general population at an overall frequency of 0.024% (68/280,840 alleles) in the Genome Aggregation Database. The asparagine at codon 41 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, in vitro functional analysis of this variant protein demonstrates severely disabled protein targeting and retention (Braiterman 2009). Based on available information, this variant is considered likely pathogenic. References: Bost M et al. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol. 2012 Jun;26(2-3):97-101. Braiterman L et al. Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B. Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G433-44. Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Deguti M et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 16, 2018 | The ATP7B c.122A>G (p.Asn41Ser) missense variant has been reported in two studies in which it is found in a compound heterozygote state in a total of three patients with Wilson disease. In one of the three patients, the p.Asn41Ser variant was detected in cis with a second missense variant and a third missense variant in trans (Deguti et al. 2004; Coffey et al. 2013). The p.Asn41Ser variant was absent from 60 controls (Deguti et al. 2004) and is reported at a frequency of 0.00048 in the European American population of the Exome Sequencing Project. Functionally, Braiterman et al. (2009) demonstrated that the p.Asn41Ser variant protein was defective in proper targeting and retention in WIF-B cells, when compared to wild type. Based on the evidence, the p.Asn41Ser variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 08, 2021 | The p.Asn41Ser variant in ATP7B has been reported in at least 3 heterozygous individuals and at least 2 compound heterozygous individuals with Wilson disease; though, 1 of these compound heterozygous individuals also carried a variant of uncertain significance in cis with the p.Asn41Ser (Deguti 2004 PMID: 15024742, Bost 2012 PMID: 22677543, Coffey 2013 PMID: 23518715, Zhao 2019 PMID: 30275481). It has also been identified in 0.047% (61/128586) of European chromosomes by gnomAD (http://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 (Braiterman 2009 PMID: 19033537). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PS3_Supporting. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 25, 2023 | This missense variant replaces asparagine with serine at codon 41 of the ATP7B protein. This variant is located in the p.Phe37_Glu45 sequence that is thought to be an essential apical targeting determinant for ATP7B in elevated copper condition and participate in the post-trans-Golgi network retention of the protein under low-copper condition (PMID: 19033537). A functional study has reported that this variant results in defective copper-induced trafficking of ATP7B protein in hepatic cells (PMID: 19033537). This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 15024742, 22677543, 22820477, 23518715, 32770663, 33640437, 36096368; ClinVar: SCV000626829.6), including at least six individuals in the compound heterozygous state or unknown phase with a second pathogenic variant in the ATP7B gene (PMID: 15024742, 22820477, 23518715, 33640437). This variant has been identified in 68/280840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
not provided Pathogenic:6
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 28, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 25, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Oct 09, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 16, 2024 | Published functional studies demonstrate this variant is associated with impaired protein trafficking and apical targeting, supporting a damaging effect (PMID: 19033537); Reported previously in patients with Wilson disease who were heterozygous for another variant in the ATP7B gene, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 15024742, 23518715, 35220961); 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: 20437613, 17919502, 21454443, 22677543, 23518715, 22898812, 31589614, 34426522, 32248359, 30275481, 30937429, 27377421, 28719003, 26740555, 27460824, 34620762, 34400371, 22820477, 30097039, 32770663, 22106832, 26986070, 33640437, 31408533, 29473088, 29063292, 31059521, 36096368, 37660282, 34405919, 15024742, 19033537, 35220961, 37895316, 37937776) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 18, 2023 | - - |
Inborn genetic diseases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 08, 2022 | The c.122A>G (p.N41S) alteration is located in exon 2 (coding exon 2) of the ATP7B gene. This alteration results from an A to G substitution at nucleotide position 122, causing the asparagine (N) at amino acid position 41 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.02% (68/280840) total alleles studied. The highest observed frequency was 0.05% (61/128586) of European (non-Finnish) alleles. The p.N41S variant has been identified in multiple patients with Wilson disease with a second pathogenic ATP7B variant detected in trans or phase unknown in at least four of the reported cases (Ben-Rebeh, 2012; Bost, 2012; Brunet, 2012; Coffey, 2013; Deguti, 2004; Woimant, 2020). This amino acid position is highly conserved in available vertebrate species. Functional studies showed the p.N41S variant impairs apical targeting, Golgi retention, and ATP7B trafficking in vitro (Braiterman, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
ATP7B-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 11, 2024 | The ATP7B c.122A>G variant is predicted to result in the amino acid substitution p.Asn41Ser. This variant has been reported, in the compound heterozygous state, in two patients affected with Wilson disease (Deguti et al. 2004. PubMed ID: 15024742; Coffey et al. 2013. PubMed ID: 23518715). In-vitro functional studies showed that this variant results in severely disabled protein targeting and retention (Braiterman et al., 2009. PubMed ID: 19033537). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/157928/). This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;T;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;M;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;D;N;N;.;D
REVEL
Uncertain
Sift
Uncertain
D;T;T;D;D;.;D
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
P;D;D;D;D;D;D
Vest4
MVP
MPC
ClinPred
T
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