rs267607507

Positions:

• chr17-44913733-C-G
• chr17-44913733-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002055.5(GFAP):​c.613G>C​(p.Glu205Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04

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]

GFAP (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.613G>C	p.Glu205Gln	missense_variant	3/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.613G>C	p.Glu205Gln	missense_variant	3/10		NP_001350775.1
GFAP	NM_001242376.3	c.613G>C	p.Glu205Gln	missense_variant	3/7		NP_001229305.1
GFAP	NM_001131019.3	c.613G>C	p.Glu205Gln	missense_variant	3/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.613G>C	p.Glu205Gln	missense_variant	3/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D;.;.;.;.;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;T;T;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.3	.;M;.;.;M;M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.4	.;.;N;.;N;.;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	.;.;D;.;D;.;.;.
Sift4G	Uncertain	0.051	.;.;T;.;T;.;T;T
Polyphen		0.92	.;P;.;.;.;.;.;.
Vest4		0.45, 0.43
MutPred		0.68		Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);.;Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);
MVP		0.99
MPC		1.1
ClinPred		0.94	D
GERP RS		3.7
Varity_R		0.75
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607507; hg19: chr17-42991101; COSMIC: COSV99493614; COSMIC: COSV99493614;