rs797044578

chr17-44913277-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002055.5(GFAP):c.772C>T(p.Arg258Cys) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 3.90

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 17-44913277-G-A is Pathogenic according to our data. Variant chr17-44913277-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 190345.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.772C>T	p.Arg258Cys	missense_variant	4/9	ENST00000588735.3
GFAP	NM_001363846.2	c.772C>T	p.Arg258Cys	missense_variant	4/10
GFAP	NM_001242376.3	c.772C>T	p.Arg258Cys	missense_variant	4/7
GFAP	NM_001131019.3	c.772C>T	p.Arg258Cys	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.772C>T	p.Arg258Cys	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:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alexander disease Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 12, 2020	A heterozygous missense variant, NM_002055.4(GFAP):c.772C>T, has been identified in exon 4 of 9 of the GFAP gene. The variant is predicted to result in a major amino acid change from arginine to cysteine at position 258 of the protein (NP_002046.1:p.Arg258Cys). The arginine residue at this position has moderate conservation (100 vertebrates, UCSC), and is located within Coil 2A of the rod functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in the gnomAD population database. This variant has been reported as pathogenic in multiple patients with Alexander disease (ClinVar, Jost, M., et al. (2017)). Additionally, transfected HeLa and US-OS cells showed abnormal protein aggregates, where significantly more cells contained these aggregates compared to controls (Tulyeu, J., et al. (2019)). A different variant in the same codon resulting in a change to proline, has also been reported in a patient with Alexander disease (ClinVar, Brenner, M., et al . (2001)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 01, 2022

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including at least one apparent de novo. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant showed protein aggregate formation in vitro in multiple human cell types (PMID: 30213442). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.80, 0.81, 0.88
MutPred		0.90		Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);.;Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);.;.;
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.79
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs797044578; hg19: chr17-42990645; COSMIC: COSV53652871; COSMIC: COSV53652871;