17-44915251-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_002055.5(GFAP):c.236G>T(p.Arg79Leu) variant causes a missense change. 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R79P) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
GFAP
NM_002055.5 missense
NM_002055.5 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 6.15
Genes affected
GFAP (HGNC:4235): (glial fibrillary acidic protein) This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_002055.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-44915252-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GFAP | NM_002055.5 | c.236G>T | p.Arg79Leu | missense_variant | 1/9 | ENST00000588735.3 | |
GFAP | NM_001363846.2 | c.236G>T | p.Arg79Leu | missense_variant | 1/10 | ||
GFAP | NM_001242376.3 | c.236G>T | p.Arg79Leu | missense_variant | 1/7 | ||
GFAP | NM_001131019.3 | c.236G>T | p.Arg79Leu | missense_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFAP | ENST00000588735.3 | c.236G>T | p.Arg79Leu | missense_variant | 1/9 | 1 | NM_002055.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: not provided
Submissions summary: Other:2
Revision: no classification provided
LINK: link
Submissions by phenotype
not provided Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Alexander disease Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.;.;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;H;H;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;.;D;D;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
.;.;D;D;.;.;.;.;.
Sift4G
Uncertain
.;.;D;D;.;D;D;.;.
Polyphen
0.14
.;B;.;.;.;.;.;.;.
Vest4
0.97, 0.97, 0.97
MutPred
Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);
MVP
1.0
MPC
0.58
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at