17-44911267-A-G

Position:

• chr17-44911267-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The ENST00000588735.3(GFAP):​c.1096T>C​(p.Tyr366His) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y366C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP ENST00000588735.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000588735.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-44911267-A-G is Pathogenic according to our data. Variant chr17-44911267-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 66434.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1096T>C	p.Tyr366His	missense_variant	6/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1096T>C	p.Tyr366His	missense_variant	6/10		NP_001350775.1
GFAP	NM_001242376.3	c.1096T>C	p.Tyr366His	missense_variant	6/7		NP_001229305.1
GFAP	NM_001131019.3	c.1096T>C	p.Tyr366His	missense_variant	6/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1096T>C	p.Tyr366His	missense_variant	6/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2023	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GFAP protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr366 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 17985264), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 66434). This missense change has been observed in individual(s) with clinical features of Alexander disease (PMID: 15732097; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 366 of the GFAP protein (p.Tyr366His). -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

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	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;H;.;.;.;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.5	.;.;D;.;.;D;.;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.99, 1.0
MutPred		0.95		Gain of disorder (P = 0.042);Gain of disorder (P = 0.042);Gain of disorder (P = 0.042);.;.;Gain of disorder (P = 0.042);Gain of disorder (P = 0.042);.;.;
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
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: rs58008462; hg19: chr17-42988635;