17-44915228-C-T

Variant names:

• chr17-44915228-C-T
• rs267607518
• NM_002055.5:c.259G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_002055.5(GFAP):​c.259G>A​(p.Val87Ile) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V87G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.73
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Alexander disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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, 14 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 chr17-44915228-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 66477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 17-44915228-C-T is Pathogenic according to our data. Variant chr17-44915228-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 190339.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.259G>A	p.Val87Ile	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.259G>A	p.Val87Ile	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.259G>A	p.Val87Ile	missense_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.259G>A	p.Val87Ile	missense_variant	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.259G>A	p.Val87Ile	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alexander disease Pathogenic:2

Jan 08, 2015

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Heterozygous Missense variant c.259G>A in Exon 1 of the GFAP gene that results in the amino acid substitution p.Val87Ile was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(variant ID 190339). This variant has been observed in many individuals affected with Alexander disease reported by (Srivastava S, et al., 1993). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

not provided Pathogenic:1

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 87 of the GFAP protein (p.Val87Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alexander disease (PMID: 21533827, 24306001; Invitae). ClinVar contains an entry for this variant (Variation ID: 190339). 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.Val87 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 21533827, 24306001), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;D;.;.;.;D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;H;.;H;H;.;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.88	.;.;N;N;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	.;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0030	.;.;D;D;.;D;D;.;.
Polyphen		0.83	.;P;.;.;.;.;.;.;.
Vest4		0.73, 0.74, 0.73
MutPred		0.73		Loss of methylation at K86 (P = 0.0571);Loss of methylation at K86 (P = 0.0571);Loss of methylation at K86 (P = 0.0571);Loss of methylation at K86 (P = 0.0571);Loss of methylation at K86 (P = 0.0571);Loss of methylation at K86 (P = 0.0571);Loss of methylation at K86 (P = 0.0571);Loss of methylation at K86 (P = 0.0571);Loss of methylation at K86 (P = 0.0571);
MVP		0.99
MPC		0.83
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		0.021	Neutral
Varity_R		0.66
gMVP		0.91
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607518; hg19: chr17-42992596;