rs797044579
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_002055.5(GFAP):c.791T>C(p.Leu264Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_002055.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GFAP | NM_002055.5 | c.791T>C | p.Leu264Pro | missense_variant | Exon 5 of 9 | ENST00000588735.3 | NP_002046.1 | |
GFAP | NM_001363846.2 | c.791T>C | p.Leu264Pro | missense_variant | Exon 5 of 10 | NP_001350775.1 | ||
GFAP | NM_001242376.3 | c.791T>C | p.Leu264Pro | missense_variant | Exon 5 of 7 | NP_001229305.1 | ||
GFAP | NM_001131019.3 | c.791T>C | p.Leu264Pro | missense_variant | Exon 5 of 8 | NP_001124491.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Alexander disease Pathogenic:1Other:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are likely mechanisms of disease in this gene and are associated with Alexander disease (MIM#203450). Functional studies have demonstrated both dominant negative and gain of function are possible mechanisms of disease, however, the latter is the more widely accepted mechanism (OMIM, PMID: 11138011, PMID: 30355500, PMID: 31484723, GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established filament domain. Many pathogenic missense variants are reported within this domain (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in two individuals with adult-onset Alexander disease (ClinVar, PMID: 24306001, PMID: 21533827). Additionally, a deletion-insertion resulting in the same protein outcome (c.791_792delinsCT) has also been reported in an individual with adult-onset Alexander disease (PMID: 20562394). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at