rs62636501

Variant names:

• chr17-44911284-T-A
• rs62636501
• NM_002055.5:c.1079A>T

Your query was ambiguous. Multiple possible variants found:

• chr17-44911284-T-A
• chr17-44911284-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_002055.5(GFAP):​c.1079A>T​(p.Asp360Val) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-44911284-T-A is Pathogenic according to our data. Variant chr17-44911284-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 66431.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1079A>T	p.Asp360Val	missense_variant	Exon 6 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1079A>T	p.Asp360Val	missense_variant	Exon 6 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.1079A>T	p.Asp360Val	missense_variant	Exon 6 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.1079A>T	p.Asp360Val	missense_variant	Exon 6 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1079A>T	p.Asp360Val	missense_variant	Exon 6 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alexander disease Pathogenic:2

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GFAP related disorder (ClinVar ID: VCV000066431, PMID:21533827 PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Alexander disease (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 08, 2015

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	.;H;.;.;.;H;H;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.2	.;.;D;.;.;D;.;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;D;.;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.98, 0.99
MutPred		0.97		Gain of ubiquitination at K356 (P = 0.0577);Gain of ubiquitination at K356 (P = 0.0577);Gain of ubiquitination at K356 (P = 0.0577);.;.;Gain of ubiquitination at K356 (P = 0.0577);Gain of ubiquitination at K356 (P = 0.0577);.;.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.99
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: rs62636501; hg19: chr17-42988652;