NM_000053.4:c.3402delC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000053.4(ATP7B):c.3402delC(p.Ala1135GlnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000431 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1134P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000053.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.3402delC | p.Ala1135GlnfsTer13 | frameshift_variant | Exon 15 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.0000642 AC: 16AN: 249374Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135328
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461814Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29AN XY: 727212
GnomAD4 genome
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:14Other:1
The ATP7B c.3402delC; p.Ala1135fs variant (rs137853281), also published as 3400delC or 3403delC, is reported in the literature in individuals with a clinical diagnosis of Wilson disease (Deguti 2004, Duc 1998, Firneisz 2002, Margarit 2005, Thomas 1995). This variant has been reported in the homozygous state and has also been reported in affected individuals carrying a second pathogenic variant (Deguti 2004). The p.Ala1135fs variant is described in the ClinVar database (Variation ID: 88958) and is observed in the Genome Aggregation Database with a low frequency of 0.01% (17/128568 alleles) in the non-Finnish European population. This variant causes a frameshift by deleting a single nucleotide, so it 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: Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 23(4):398. Duc HH et al. His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype. Eur J Hum Genet. 1998 Nov-Dec;6(6):616-23. Firneisz G et al. Common mutations of ATP7B in Wilson disease patients from Hungary. Am J Med Genet. 2002 Feb 15;108(1):23-8. 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. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. -
- -
- -
Variant summary: ATP7B c.3402delC (p.Ala1135GlnfsX13) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 6.4e-05 in 249374 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.3402delC has been reported in the literature in multiple individuals affected with Wilson Disease (Balashova_2019, Naorniakowska 2016, Gromadzka 2005, Caca 2001, Tanzi 1993). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated subcellular mislocalization (Huster_2003). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
- -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -
The p.Ala1135GlnfsX13 variant in ATP7B has been reported in many individuals with Wilson disease, including >20 homozygotes and >20 compound heterozygotes (Bem 2013, Caca 2001, Deguti2004, Firneisz 2002, Gromadzka 2005, Haas 1999, Kluska 2019, Kucisnskas 2008, Margarit 2005, Paradisi 2015, Tanzi 1993, Waldenstrom 1996). It has also been identified in 0.01% (17/128568) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is a low enough freuqncy to be consistent with a recessive Wilson disease allele. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1135 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of ATP7B is an established disease mechanism for 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, PM2. -
The ATP7B c.3402delC (p.Ala1135GlnfsTer13) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Ala1135GlnfsTer13 variant has been reported in seven studies in which it is found in a total of 80 patients with Wilson disease, including in 24 in a homozygous state, in 48 in a compound heterozygous state and in eight in a heterozygous state (Tanzi et al. 1993; Deguti et al. 2004; Gromadzka et al. 2005; Kucinskas et al. 2008; Machado et al. 2008; Bem et al. 2013; Paradisi et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Ala1135GlnfsTer13 variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
This variant deletes 1 nucleotide in exon 15 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant disrupts intracellular localization (PMID: 12557139). This variant has been reported in the homozygous state or with a co-occurring pathogenic ATP7B variant in many individuals affected with Wilson disease and has been described as a common mutation in German, Brazilian, Polish, Venezuelan, and Russian populations (PMID: 8298641, 11690702, 15024742, 16283883, 25497208, 31708252, 34400371, 35169583). This variant has been identified in 17/280726 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. -
Criteria applied: PVS1,PM3,PM2_SUP; Identified as compund heterozygous with NM_000053.4:c.3207C>A -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000088958 / PMID: 8298641). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
- -
This sequence change creates a premature translational stop signal (p.Ala1135Glnfs*13) 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 (rs137853281, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 8298641, 15024742, 16283883, 25497208). ClinVar contains an entry for this variant (Variation ID: 88958). For these reasons, this variant has been classified as Pathogenic. -
- -
- -
not provided Pathogenic:5
- -
ATP7B: PVS1, PM2, PM3 -
- -
- -
Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25497208, 31589614, 34400371, 32270360, 32043565, 11690702, 15967699, 23982005, 20082719, 23789284, 8533760, 11857545, 26819605, 12557139, 31708252, 32067425, 8298641, 18855987, 33159804, 15024742) -
Inborn genetic diseases Pathogenic:1
The c.3402delC (p.A1135Qfs*13) alteration, located in exon 15 (coding exon 15) of the ATP7B gene, consists of a deletion of one nucleotide at position 3402, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.3402delC allele has an overall frequency of 0.006% (17/280726) total alleles studied. The highest observed frequency was 0.013% (17/128568) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other ATP7B variant(s) in individual(s) with features consistent with Wilson disease (Deguti, 2004; Gromadzka, 2005; Paradisi, 2015). Based on the available evidence, this alteration is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at