rs779904655
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000053.4(ATP7B):c.2009_2015delATATGCT(p.Tyr670fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000053.4 frameshift
Scores
Clinical Significance
Conservation
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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.2009_2015delATATGCT | p.Tyr670fs | frameshift_variant | Exon 7 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249204Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135188
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461648Hom.: 0 AF XY: 0.0000234 AC XY: 17AN XY: 727134
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:12
This variant deletes 7 nucleotides in exon 7 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. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 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. -
This variant deletes 7 nucleotides in exon 7 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. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 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. -
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The ATP7B c.2009_2015del; p.Tyr670Ter variant (rs779904655), also known as 1950-1956 deletion, has been described in individuals and families affected with Wilson disease (Bull 1993, Thomas 1995). The variant is reported in ClinVar (Variation ID: 188862), and is observed in the general population at an overall frequency of 0.0024% (6/249204 alleles) in the Genome Aggregation Database. This variant deletes seven nucleotides resulting in an immediate stop codon, 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 Bull PC et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993 Dec;5(4):327-37. PMID: 8298639. Thomas GR et al. Wilson disease in Iceland: a clinical and genetic study. Am J Hum Genet. 1995 May;56(5):1140-6. PMID: 7726170. -
This sequence change creates a premature translational stop signal (p.Tyr670*) 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 (rs779904655, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 7726170). It has also been observed to segregate with disease in related individuals. This variant is also known as 2010del7. ClinVar contains an entry for this variant (Variation ID: 188862). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: The ATP7B c.2009_2015delATATGCT (p.Tyr670Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B 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 (e.g. c.3402delC, p.Ala1135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120512 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in affected individuals in the literature in both the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
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The variant NM_000053.4:c.2009_2015del (chr13:51960253) in ATP7B was detected in 619 heterozygotes and 4 homozygotes out of 58K WGS Icelanders (MAF= 0,541%). Following imputation in a set of 166K Icelanders (1,782 imputed heterozygotes and 7 imputed homozygotes) we observed an association with disorders of copper metabolism (ICD10 code: E830) under a recessive model using 26 cases and 302580 controls (OR= 244.2, P= 1.9e-18). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. -
The p.Tyr670X variant in ATP7B has been reported in at least 2 homozygous individuals with Wilson disease and segregated with disease in 4 affected individuals from 2 families (Bull 1993, Thomas 1995, Curtis 1999). It has also been identified in 0.005% (6/112946) of chromosomes in Europeans by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 188862). This deletion leads to a premature termination codon at position 670 , 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, PP1_Strong, PM2, PM3, PP4. -
not provided Pathogenic:3
ATP7B: PVS1, PP1:Strong, PM2, PM3 -
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7726170, 8298639, 10502777) -
PP4, PM2_moderate, PM3, PVS1 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at