rs59565950

Positions:

• chr17-44913333-C-A
• chr17-44913333-C-G
• chr17-44913333-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_002055.5(GFAP):​c.716G>T​(p.Arg239Leu) 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:2
• Conservation: PhyloP100: 7.91

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]

GFAP (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 17-44913333-C-A is Pathogenic according to our data. Variant chr17-44913333-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 66498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.716G>T	p.Arg239Leu	missense_variant	4/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.716G>T	p.Arg239Leu	missense_variant	4/10		NP_001350775.1
GFAP	NM_001242376.3	c.716G>T	p.Arg239Leu	missense_variant	4/7		NP_001229305.1
GFAP	NM_001131019.3	c.716G>T	p.Arg239Leu	missense_variant	4/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.716G>T	p.Arg239Leu	missense_variant	4/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 18, 2022	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 239 of the GFAP protein (p.Arg239Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alexander disease (PMID: 17043438, 21041050, 34146839). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66498). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Arg239 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11138011, 11587071). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Alexander disease Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	.;H;.;.;H;H;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.5	.;.;D;.;D;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;.;D;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.98
MutPred		0.97		Loss of disorder (P = 0.068);Loss of disorder (P = 0.068);Loss of disorder (P = 0.068);.;Loss of disorder (P = 0.068);Loss of disorder (P = 0.068);Loss of disorder (P = 0.068);.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.98

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: rs59565950; hg19: chr17-42990701;