17-44915105-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:2

Conservation

PhyloP100: 5.01

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.382G>A	p.Asp128Asn	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.382G>A	p.Asp128Asn	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.382G>A	p.Asp128Asn	missense_variant	Exon 1 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.382G>A	p.Asp128Asn	missense_variant	Exon 1 of 8		NP_001124491.1	P14136-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.382G>A	p.Asp128Asn	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461004

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726882

show subpopulations

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.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alexander disease

Pathogenic:2Other:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Lifecell International Pvt. Ltd

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided

Pathogenic:1Other:1

Dec 20, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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). Experimental studies have shown that this variant affects GFAP protein function (PMID: 28882119). For these reasons, this variant has been classified as Pathogenic. -

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

.;D;.;.;.;.;D;.;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.9

.;M;.;.;M;M;.;.;.;.

PrimateAI

Uncertain

0.52

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over