rs267607509

Positions:

• chr17-44915105-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.382G>A​(p.Asp128Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 5.01

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, 0.981
• PP5: Variant 17-44915105-C-T is Pathogenic according to our data. Variant chr17-44915105-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66484.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.382G>A	p.Asp128Asn	missense_variant	1/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.382G>A	p.Asp128Asn	missense_variant	1/10		NP_001350775.1
GFAP	NM_001242376.3	c.382G>A	p.Asp128Asn	missense_variant	1/7		NP_001229305.1
GFAP	NM_001131019.3	c.382G>A	p.Asp128Asn	missense_variant	1/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.382G>A	p.Asp128Asn	missense_variant	1/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461004 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alexander disease Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.382G>A in Exon 1 of the GFAP gene that results in the amino acid substitution p.Asp128Asn 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 high, 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: 66484).This disorder has previously been reported in the patient affected with autism (Nykamp K, et. al 2017). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are suggested as mechanisms of disease in this gene and are associated with Alexander disease (MIM#203450). Functional studies have demonstrated both dominant negative and gain of function are possible mechanisms of disease, however, the latter is the most widely accepted mechanism (OMIM, PMIDs: 11138011, 30355500, 31484723). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated filament domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with adult onset Alexander disease (PMIDs: 28882119, 18684770, 25997626, 30942895). In addition, it has been reported as pathogenic and likely pathogenic by two clinical laboratories (ClinVar). (SP) 0903 - This variant has limited evidence for segregation with disease. It has been shown to segregate with disease in a family with at least four affected relatives with Alexander disease (PMID: 28882119). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to increase GFAP aggregations in zebrafish as compared to wild-type (PMID: 28882119). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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	Dec 20, 2020	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects GFAP protein function (PMID: 28882119). This variant has been observed in individual(s) with Alexander disease (PMID: 18684770, 28882119, 25997626). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66484). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 128 of the GFAP protein (p.Asp128Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;D;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.9	.;M;.;.;M;M;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	.;.;D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	.;.;D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0060	.;.;D;.;D;.;D;D;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.
Vest4		0.57, 0.58, 0.55
MutPred		0.87		Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);.;Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.90
gMVP		0.76

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: rs267607509; hg19: chr17-42992473; COSMIC: COSV99493073; COSMIC: COSV99493073;