rs267607514

Positions:

• chr17-44911369-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_002055.5(GFAP):​c.994G>A​(p.Glu332Lys) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 3.42

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 9 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, 0.981
• PP5: Variant 17-44911369-C-T is Pathogenic according to our data. Variant chr17-44911369-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 66515.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.994G>A	p.Glu332Lys	missense_variant	6/9	ENST00000588735.3
GFAP	NM_001363846.2	c.994G>A	p.Glu332Lys	missense_variant	6/10
GFAP	NM_001242376.3	c.994G>A	p.Glu332Lys	missense_variant	6/7
GFAP	NM_001131019.3	c.994G>A	p.Glu332Lys	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.994G>A	p.Glu332Lys	missense_variant	6/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Alexander disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GeneReviews

Jan 08, 2015

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;.;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.9	.;M;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.5	.;.;D;.;D;.
REVEL	Pathogenic	0.84
Sift	Benign	0.031	.;.;D;.;D;.
Sift4G	Uncertain	0.033	.;.;D;.;D;.
Polyphen		0.97	.;D;.;.;.;.
Vest4		0.92, 0.91
MutPred		0.91		Gain of ubiquitination at E332 (P = 0.0039);Gain of ubiquitination at E332 (P = 0.0039);Gain of ubiquitination at E332 (P = 0.0039);.;Gain of ubiquitination at E332 (P = 0.0039);Gain of ubiquitination at E332 (P = 0.0039);
MVP		1.0
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.87
gMVP		0.98

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: rs267607514; hg19: chr17-42988737;