rs61622935

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_002055.5(GFAP):c.262C>T(p.Arg88Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R88S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:2

Conservation

PhyloP100: 9.78

Publications

25 publications found

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 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

GFAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr17-44915225-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16173.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 17-44915225-G-A is Pathogenic according to our data. Variant chr17-44915225-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16172.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.262C>T	p.Arg88Cys	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.262C>T	p.Arg88Cys	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.262C>T	p.Arg88Cys	missense_variant	Exon 1 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.262C>T	p.Arg88Cys	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.262C>T	p.Arg88Cys	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alexander disease

Pathogenic:5Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 28, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP3 supporting -

Jan 03, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016172, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17318298, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942, 3CNET: 0.966, PP3_P). A missense variant is a common mechanism associated with Alexander disease (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported to be associated with GFAP related disorder (ClinVar ID: VCV000016173, PM5_P).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 01, 2025

Center of Human Genetics, Hôpital Erasme

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 20, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17629821, 16505300, 34865968, 36088400, 17318298, 11567214, 26478912, 15477559, 15732097, 12034785, 18079314, 16217707, 17894839, 34146839, 35831840, 31069529, 36601294) -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 88 of the GFAP protein (p.Arg88Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alexander disease (PMID: 11567214, 15732097, 26478912). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16172). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GFAP protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GFAP: PM6:Strong, PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -

Sep 30, 2019

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. 10 de novo cases with parental identity not confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

.;H;.;H;H;.;.;.;.

PhyloP100

9.8

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.8

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

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.95, 0.96

MutPred

0.95

Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);

MVP

1.0

MPC

1.4

ClinPred

1.0

GERP RS

4.7

PromoterAI

-0.038

Neutral

(source)

Varity_R

0.83

gMVP

0.95

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over