rs267607516
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_002055.5(GFAP):c.302T>C(p.Leu101Pro) 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
GFAP
NM_002055.5 missense
NM_002055.5 missense
Scores
9
3
1
Clinical Significance
Conservation
PhyloP100: 7.28
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 8 ACMG points.
PM1
?
In a region_of_interest Coil 1A (size 31) in uniprot entity GFAP_HUMAN there are 23 pathogenic changes around while only 4 benign (85%) in NM_002055.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.989
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GFAP | NM_002055.5 | c.302T>C | p.Leu101Pro | missense_variant | 1/9 | ENST00000588735.3 | |
GFAP | NM_001363846.2 | c.302T>C | p.Leu101Pro | missense_variant | 1/10 | ||
GFAP | NM_001242376.3 | c.302T>C | p.Leu101Pro | missense_variant | 1/7 | ||
GFAP | NM_001131019.3 | c.302T>C | p.Leu101Pro | missense_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFAP | ENST00000588735.3 | c.302T>C | p.Leu101Pro | 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: Uncertain significance
Submissions summary: Uncertain:1Other:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
GFAP-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 06, 2023 | The GFAP c.302T>C variant is predicted to result in the amino acid substitution p.Leu101Pro. This variant has been reported in an individual with adult-onset Alexander disease; functional studies showed it may affect the solubility of GFAP (Kaneko et al 2009. PubMed ID: 19412928). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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
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
Uncertain
T
Polyphen
1.0
.;D;.;.;.;.;.;.;.
Vest4
0.93, 0.95, 0.95
MutPred
Gain of disorder (P = 0.0389);Gain of disorder (P = 0.0389);Gain of disorder (P = 0.0389);Gain of disorder (P = 0.0389);Gain of disorder (P = 0.0389);Gain of disorder (P = 0.0389);Gain of disorder (P = 0.0389);Gain of disorder (P = 0.0389);Gain of disorder (P = 0.0389);
MVP
0.97
MPC
1.6
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