chr20-25300853-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePM2BS1_Supporting
The NM_001042472.3(ABHD12):c.1189C>T(p.Gln397*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000254 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. 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_001042472.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249168Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135276
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461766Hom.: 0 Cov.: 34 AF XY: 0.0000316 AC XY: 23AN XY: 727186
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
This sequence change results in a premature translational stop signal in the ABHD12 gene (p.Gln397*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acids of the ABHD12 protein. This variant is present in population databases (rs745990956, ExAC 0.006%). This variant has not been reported in the literature in individuals with ABHD12-related conditions. ClinVar contains an entry for this variant (Variation ID: 191159). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Downgraded to LB based on updated frequency in local population -
not specified Uncertain:1
Variant summary: ABHD12 c.1189C>T (p.Gln397X) results in a premature termination codon and although it is not predicted to result in absence of the protein due to nonsense mediated decay, it is expected to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. However, variants downstream of this position have not been classified pathogenic in ClinVar or by our lab. The variant allele was found at a frequency of 3.6e-05 in 249168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1189C>T has been reported in the literature in the homozygous state in an individual with no apparent symptoms of PHARC (Shamia_2015); however, due to the slowly progressive nature of the disorder and variable phenotype, pathogenicity cannot be ruled out. This report does not provide unequivocal conclusions about association of the variant with PHARC syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26141664). ClinVar contains an entry for this variant (Variation ID: 191159). Based on the evidence outlined above, the variant was classified as uncertain significance. -
PHARC syndrome Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at