dbSNP rs61497286: GFAP:p.Ala244Val (chr17-44913318-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_002055.5(GFAP):c.731C>T(p.Ala244Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

not provided no classification provided O:2

Conservation

PhyloP100: 1.66

Publications

7 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, 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 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_002055.5

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFAP	NM_002055.5	MANE Select	c.731C>T	p.Ala244Val	missense	Exon 4 of 9	NP_002046.1	P14136-1
GFAP	NM_001363846.2		c.731C>T	p.Ala244Val	missense	Exon 4 of 10	NP_001350775.1	A0A1X7SBR3
GFAP	NM_001242376.3		c.731C>T	p.Ala244Val	missense	Exon 4 of 7	NP_001229305.1	P14136-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFAP	ENST00000588735.3	TSL:1 MANE Select	c.731C>T	p.Ala244Val	missense	Exon 4 of 9	ENSP00000466598.2	P14136-1
GFAP	ENST00000591327.2	TSL:1	n.1885C>T		non_coding_transcript_exon	Exon 2 of 5
GFAP	ENST00000639277.1	TSL:5	c.731C>T	p.Ala244Val	missense	Exon 4 of 10	ENSP00000492432.1	A0A1W2PR46

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alexander disease (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.74

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.5

PhyloP100

1.7

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.69

Sift

Benign

0.074

Sift4G

Benign

0.14

Polyphen

0.74

Vest4

0.65

MutPred

0.72

Loss of disorder (P = 0.0588)

MVP

1.0

MPC

0.98

ClinPred

0.88

GERP RS

4.9

Varity_R

0.27

gMVP

0.56

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: 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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over