rs61733679
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000053.4(ATP7B):c.3369G>A(p.Pro1123Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000626 in 1,614,158 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000053.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3369G>A | p.Pro1123Pro | synonymous_variant | Exon 15 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00331 AC: 504AN: 152164Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000850 AC: 212AN: 249552Hom.: 0 AF XY: 0.000583 AC XY: 79AN XY: 135400
GnomAD4 exome AF: 0.000343 AC: 501AN: 1461876Hom.: 1 Cov.: 32 AF XY: 0.000290 AC XY: 211AN XY: 727244
GnomAD4 genome AF: 0.00334 AC: 509AN: 152282Hom.: 2 Cov.: 32 AF XY: 0.00338 AC XY: 252AN XY: 74448
ClinVar
Submissions by phenotype
Wilson disease Uncertain:1Benign:6
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Benign:2
Variant summary: The ATP7B c.3369G>A (p.Pro1123Pro) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 135/120756 (1/894), predominantly in the African cohort, 118/9800 (1/83), which exceeds the estimated maximal expected allele frequency for a pathogenic ATP7B variant of 1/1851. Therefore, suggesting the variant of interest is a common polymorphism found in population(s) of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. A reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as likely benign until additional information becomes available. -
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not specified Benign:1
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at