NM_002055.5:c.1126C>T

Variant names:

• chr17-44911237-G-A
• rs267607512
• NM_002055.5:c.1126C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. 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 Likely 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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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 rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	Exon 6 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	Exon 6 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.1126C>T	p.Arg376Trp	missense_variant, splice_region_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.1126C>T	p.Arg376Trp	missense_variant, splice_region_variant	Exon 6 of 9	1	NM_002055.5	ENSP00000466598.2

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

Dec 06, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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). Experimental studies have shown that this variant affects GFAP protein function (PMID: 27648269). 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. For these reasons, this variant has been classified as Pathogenic. -

Alexander disease Other:1

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GeneReviews

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	0.93
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;.;.;D;.
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
MutationAssessor	Pathogenic	3.6	.;H;.;.;.;H;H;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.1	.;.;D;.;.;D;.;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;.;D;.;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.;D;.;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;