17-44911743-T-C

Position:

• chr17-44911743-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_002055.5(GFAP):​c.835A>G​(p.Lys279Glu) 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 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: 8.02

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a region_of_interest Coil 2B (size 120) in uniprot entity GFAP_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.835A>G	p.Lys279Glu	missense_variant	5/9	ENST00000588735.3
GFAP	NM_001363846.2	c.835A>G	p.Lys279Glu	missense_variant	5/10
GFAP	NM_001242376.3	c.835A>G	p.Lys279Glu	missense_variant	5/7
GFAP	NM_001131019.3	c.835A>G	p.Lys279Glu	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.835A>G	p.Lys279Glu	missense_variant	5/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

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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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	.;M;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	.;.;D;.;D;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;D;.;.;.;.
Sift4G	Uncertain	0.0020	.;.;D;.;D;.;D;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.87, 0.86, 0.93
MutPred		0.87		Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);.;Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);.;.;
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.96
gMVP		0.99

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: rs58536923; hg19: chr17-42989111;