rs797044573
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_002055.5(GFAP):c.256A>G(p.Lys86Glu) 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. K86R) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
GFAP
NM_002055.5 missense
NM_002055.5 missense
Scores
10
2
1
Clinical Significance
Conservation
PhyloP100: 6.10
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_002055.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.922
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GFAP | NM_002055.5 | c.256A>G | p.Lys86Glu | missense_variant | 1/9 | ENST00000588735.3 | |
GFAP | NM_001363846.2 | c.256A>G | p.Lys86Glu | missense_variant | 1/10 | ||
GFAP | NM_001242376.3 | c.256A>G | p.Lys86Glu | missense_variant | 1/7 | ||
GFAP | NM_001131019.3 | c.256A>G | p.Lys86Glu | missense_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFAP | ENST00000588735.3 | c.256A>G | p.Lys86Glu | 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:1
Revision: no classification provided
LINK: link
Submissions by phenotype
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
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
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
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
T
Polyphen
0.87
.;P;.;.;.;.;.;.;.
Vest4
0.86, 0.87, 0.88
MutPred
Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);
MVP
1.0
MPC
1.4
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