17-44913318-G-A

Position:

• chr17-44913318-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The ENST00000588735.3(GFAP):​c.731C>T​(p.Ala244Val) 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: 32)
• Consequence: GFAP ENST00000588735.3 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: 1.66

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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in ENST00000588735.3
• 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.731C>T	p.Ala244Val	missense_variant	4/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.731C>T	p.Ala244Val	missense_variant	4/10		NP_001350775.1
GFAP	NM_001242376.3	c.731C>T	p.Ala244Val	missense_variant	4/7		NP_001229305.1
GFAP	NM_001131019.3	c.731C>T	p.Ala244Val	missense_variant	4/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.731C>T	p.Ala244Val	missense_variant	4/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

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- -

Alexander disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;D;.;.;.;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.5	.;L;.;.;L;L;.;.
MutationTaster	Benign	0.86	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	.;.;N;.;N;.;.;.
REVEL	Pathogenic	0.69
Sift	Benign	0.074	.;.;T;.;T;.;.;.
Sift4G	Benign	0.14	.;.;T;.;T;.;T;.
Polyphen		0.74	.;P;.;.;.;.;.;.
Vest4		0.65, 0.64, 0.76
MutPred		0.72		Loss of disorder (P = 0.0588);Loss of disorder (P = 0.0588);Loss of disorder (P = 0.0588);.;Loss of disorder (P = 0.0588);Loss of disorder (P = 0.0588);Loss of disorder (P = 0.0588);.;
MVP		1.0
MPC		0.98
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.27
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61497286; hg19: chr17-42990686;