rs267607519

Positions:

• chr17-44913310-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002055.5(GFAP):​c.739T>C​(p.Ser247Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: -0.332

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.739T>C	p.Ser247Pro	missense_variant	4/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.739T>C	p.Ser247Pro	missense_variant	4/10		NP_001350775.1
GFAP	NM_001242376.3	c.739T>C	p.Ser247Pro	missense_variant	4/7		NP_001229305.1
GFAP	NM_001131019.3	c.739T>C	p.Ser247Pro	missense_variant	4/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.739T>C	p.Ser247Pro	missense_variant	4/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:2

Revision: no classification provided

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;.;.;.;.;.;D;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.0	.;M;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	.;.;D;.;D;.;.;.;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0050	.;.;D;.;D;.;.;.;.
Sift4G	Uncertain	0.028	.;.;D;.;D;.;D;.;.
Polyphen		0.60	.;P;.;.;.;.;.;.;.
Vest4		0.81, 0.80, 0.89
MutPred		0.56		Loss of phosphorylation at S247 (P = 0.0861);Loss of phosphorylation at S247 (P = 0.0861);Loss of phosphorylation at S247 (P = 0.0861);.;Loss of phosphorylation at S247 (P = 0.0861);Loss of phosphorylation at S247 (P = 0.0861);Loss of phosphorylation at S247 (P = 0.0861);.;.;
MVP		1.0
MPC		1.1
ClinPred		0.94	D
GERP RS		2.6
Varity_R		0.93
gMVP		0.96

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: rs267607519; hg19: chr17-42990678;