17-44915278-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP3_StrongPP5BS2
The NM_002055.5(GFAP):c.209G>A(p.Arg70Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002055.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GFAP | NM_002055.5 | c.209G>A | p.Arg70Gln | missense_variant | Exon 1 of 9 | ENST00000588735.3 | NP_002046.1 | |
GFAP | NM_001363846.2 | c.209G>A | p.Arg70Gln | missense_variant | Exon 1 of 10 | NP_001350775.1 | ||
GFAP | NM_001242376.3 | c.209G>A | p.Arg70Gln | missense_variant | Exon 1 of 7 | NP_001229305.1 | ||
GFAP | NM_001131019.3 | c.209G>A | p.Arg70Gln | missense_variant | Exon 1 of 8 | NP_001124491.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251320Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461828Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727226
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152352Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74498
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2Other:1
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Identified in an adult patient with bulbar and/or pseudobulbar signs, ataxia, and brainstem abnormalities, contrast enhancement, and spinal cord abnormalities noted on MRI in the published literature; the variant was absent in the mother however the father was not tested (Caroli et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17894839, 27535533, 20301351, 18684770, 29421207, 26478912, 23430549) -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 70 of the GFAP protein (p.Arg70Gln). This variant is present in population databases (rs267607510, gnomAD 0.007%). This missense change has been observed in individual(s) with Alexander disease (PMID: 17894839). This missense change has been observed in at least one individual who was not affected with GFAP-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 66461). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GFAP protein function. This variant disrupts the p.Arg70 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16240361, 17438228, 17894839, 20849398). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Alexander disease Pathogenic:1Other:1
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This missense change is one of the common variants causing the adult form of Alexander Disease (PMID: 20301351, 17894839, 18684770, 18495313, 18388212, 24306001). Disease onset is typically in the third decade in described cases with the same variant (PMID: 36088400). This variant is observed in a patient with adult-onset spastic quadriparesis. MRI showed atrophic medulla with narrowed cervical cord. This variant is present in a heterozygous state at a very low frequency in control population (gnomAD). It is located in a mutational hotspot and within the functional IF rod domain in the special “head” region. Another amino acid change in the same codon has been reported as disease causing (ClinVar ID: 66460). In silico analysis by REVEL predicts the effect of the variant as uncertain (REVEL:0.607), MetaRNN as pathogenic (0.953). The current evidence available allows a classification of the variant as “likely pathogenic” (ACMG criteria: PM1, PM5, PS4_moderate, PM2_supporting). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at