Genetic Variant GFAP:p.Arg376Gly (chr17-44911237-G-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_002055.5(GFAP):c.1126C>G(p.Arg376Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

GFAP
NM_002055.5 missense, splice_region

Scores

Splicing: ADA: 0.01040

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 1.85

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr17-44911237-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 66443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 17-44911237-G-C is Pathogenic according to our data. Variant chr17-44911237-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 66442.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1126C>G	p.Arg376Gly	missense splice_region	Exon 6 of 9	NP_002046.1	P14136-1
GFAP	NM_001363846.2		c.1126C>G	p.Arg376Gly	missense splice_region	Exon 6 of 10	NP_001350775.1	A0A1X7SBR3
GFAP	NM_001242376.3		c.1126C>G	p.Arg376Gly	missense splice_region	Exon 6 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.1126C>G	p.Arg376Gly	missense splice_region	Exon 6 of 9	ENSP00000466598.2	P14136-1
GFAP	ENST00000585543.6	TSL:1	n.279C>G		splice_region non_coding_transcript_exon	Exon 1 of 4
GFAP	ENST00000591327.2	TSL:1	n.2280C>G		splice_region non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.6

PhyloP100

1.8

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.96

MutPred

0.84

Loss of stability (P = 0.0559)

MVP

0.99

MPC

1.4

ClinPred

1.0

GERP RS

2.0

PromoterAI

0.0066

Neutral

(source)

Varity_R

0.96

gMVP

0.91

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.010

dbscSNV1_RF

Benign

0.15

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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