rs61726470

Positions:

• chr17-44913291-G-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.758C>G​(p.Ala253Gly) 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 (★). Synonymous variant affecting the same amino acid position (i.e. A253A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 10.0

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, 0.981
• PP5: Variant 17-44913291-G-C is Pathogenic according to our data. Variant chr17-44913291-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 66502.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.758C>G	p.Ala253Gly	missense_variant	4/9	ENST00000588735.3
GFAP	NM_001363846.2	c.758C>G	p.Ala253Gly	missense_variant	4/10
GFAP	NM_001242376.3	c.758C>G	p.Ala253Gly	missense_variant	4/7
GFAP	NM_001131019.3	c.758C>G	p.Ala253Gly	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.758C>G	p.Ala253Gly	missense_variant	4/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2021	Reported previously in association with Alexander disease (Li et al., 2005; van der Knaap et al., 2005); Published functional studies demonstrate that this variant disrupts filament formation and results in protein aggregates (Li et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15732097, 15732098, 27648269) -

Alexander disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;.;.;.;D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;H;H;.;.;.
MutationTaster	Benign	0.71	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	.;.;D;.;D;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	.;.;D;.;D;.;.;.;.
Sift4G	Uncertain	0.032	.;.;D;.;D;.;D;.;.
Polyphen		0.045	.;B;.;.;.;.;.;.;.
Vest4		0.63, 0.62, 0.60
MutPred		0.91		Loss of glycosylation at S248 (P = 0.1224);Loss of glycosylation at S248 (P = 0.1224);Loss of glycosylation at S248 (P = 0.1224);.;Loss of glycosylation at S248 (P = 0.1224);Loss of glycosylation at S248 (P = 0.1224);Loss of glycosylation at S248 (P = 0.1224);.;.;
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.71

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: rs61726470; hg19: chr17-42990659;