Genetic Variant GFAP:p.Ala267Thr (chr17-44911779-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_002055.5(GFAP):c.799G>A(p.Ala267Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,258 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A267P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.94

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002055.5

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GFAP	NM_002055.5 link	c.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2 link	c.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 7		NP_001229305.1
GFAP	NM_001131019.3 link	c.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461258

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111876

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

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

Eigen

Benign

0.083

Eigen_PC

Benign

0.070

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.59

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

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

0.99

.;L;.;.;L;L;.;.;.

PhyloP100

4.9

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.3

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

REVEL

Uncertain

0.55

Sift

Uncertain

0.017

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

Sift4G

Uncertain

0.035

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

Polyphen

0.90

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

Vest4

0.44, 0.43, 0.41

MutPred

0.57

Gain of phosphorylation at A267 (P = 0.0277);Gain of phosphorylation at A267 (P = 0.0277);Gain of phosphorylation at A267 (P = 0.0277);.;Gain of phosphorylation at A267 (P = 0.0277);Gain of phosphorylation at A267 (P = 0.0277);Gain of phosphorylation at A267 (P = 0.0277);.;.;

MVP

1.0

MPC

0.55

ClinPred

0.92

GERP RS

4.4

PromoterAI

0.013

Neutral

(source)

Varity_R

0.37

gMVP

0.82

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