rs267607512

Positions:

• chr17-44911237-G-A
• chr17-44911237-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002055.5(GFAP):​c.1126C>T​(p.Arg376Trp) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense, splice_region
• Scores: Splicing: ADA: 0.02079
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:2
• Conservation: PhyloP100: 1.85

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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44911237-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 66442.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 17-44911237-G-A is Pathogenic according to our data. Variant chr17-44911237-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	6/9	ENST00000588735.3
GFAP	NM_001363846.2	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	6/10
GFAP	NM_001242376.3	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	6/7
GFAP	NM_001131019.3	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	6/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 25, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg376 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 21917775), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects GFAP protein function (PMID: 27648269). This variant has been observed in individual(s) with Alexander disease (PMID: 18217876, 21533827, 23149175, 27468269, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66443). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 376 of the GFAP protein (p.Arg376Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2021	Published functional studies suggest a damaging effect (Boczek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23149175, 18217876, 27648269, 21533827, 21917775) -

Alexander disease Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	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	0.82	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.95, 0.95
MutPred		0.94		Loss of disorder (P = 0.0421);Loss of disorder (P = 0.0421);Loss of disorder (P = 0.0421);.;.;Loss of disorder (P = 0.0421);Loss of disorder (P = 0.0421);.;.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		2.0
Varity_R		0.93
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.021
dbscSNV1_RF	Benign	0.16
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: rs267607512; hg19: chr17-42988605;