dbSNP rs267607507: GFAP:p.Glu205Gln (chr17-44913733-C-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_002055.5(GFAP):c.613G>C(p.Glu205Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E205K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.04

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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 chr17-44913733-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 66488.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.613G>C	p.Glu205Gln	missense_variant	Exon 3 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.613G>C	p.Glu205Gln	missense_variant	Exon 3 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.613G>C	p.Glu205Gln	missense_variant	Exon 3 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.613G>C	p.Glu205Gln	missense_variant	Exon 3 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.613G>C	p.Glu205Gln	missense_variant	Exon 3 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D;D;T;T;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.78

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

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.3

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

PhyloP100

5.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.4

.;.;N;.;N;.;.;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.051

.;.;T;.;T;.;T;T

Polyphen

0.92

.;P;.;.;.;.;.;.

Vest4

0.45, 0.43

MutPred

0.68

Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);.;Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);

MVP

0.99

MPC

1.1

ClinPred

0.94

GERP RS

3.7

Varity_R

0.75

gMVP

0.60

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

Computational scores

Splicing

Publications

Other links and lift over