rs1126642

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002055.5(GFAP):c.883G>A(p.Asp295Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0421 in 1,613,504 control chromosomes in the GnomAD database, including 1,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.036 ( 152 hom., cov: 33)

Exomes 𝑓: 0.043 ( 1695 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 6.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003569454).

BP6

Variant 17-44911695-C-T is Benign according to our data. Variant chr17-44911695-C-T is described in ClinVar as [Benign]. Clinvar id is 66509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44911695-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.883G>A	p.Asp295Asn	missense_variant	Exon 5 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.883G>A	p.Asp295Asn	missense_variant	Exon 5 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.883G>A	p.Asp295Asn	missense_variant	Exon 5 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.883G>A	p.Asp295Asn	missense_variant	Exon 5 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.883G>A	p.Asp295Asn	missense_variant	Exon 5 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

AF:

0.0356

AC:

5419

AN:

152234

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0223

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0279

Gnomad ASJ

AF:

0.0478

Gnomad EAS

AF:

0.141

Gnomad SAS

AF:

0.0602

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0393

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.0454

AC:

11291

AN:

248574

Hom.:

391

AF XY:

0.0458

AC XY:

6161

AN XY:

134604

show subpopulations

Gnomad AFR exome

AF:

0.0211

Gnomad AMR exome

AF:

0.0417

Gnomad ASJ exome

AF:

0.0461

Gnomad EAS exome

AF:

0.143

Gnomad SAS exome

AF:

0.0580

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.0373

Gnomad OTH exome

AF:

0.0353

GnomAD4 exome

AF:

0.0428

AC:

62509

AN:

1461152

Hom.:

1695

Cov.:

AF XY:

0.0428

AC XY:

31148

AN XY:

726966

show subpopulations

Gnomad4 AFR exome

AF:

0.0198

Gnomad4 AMR exome

AF:

0.0428

Gnomad4 ASJ exome

AF:

0.0454

Gnomad4 EAS exome

AF:

0.147

Gnomad4 SAS exome

AF:

0.0566

Gnomad4 FIN exome

AF:

0.0145

Gnomad4 NFE exome

AF:

0.0401

Gnomad4 OTH exome

AF:

0.0421

GnomAD4 genome

AF:

0.0356

AC:

5428

AN:

152352

Hom.:

152

Cov.:

AF XY:

0.0349

AC XY:

2603

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0223

Gnomad4 AMR

AF:

0.0286

Gnomad4 ASJ

AF:

0.0478

Gnomad4 EAS

AF:

0.141

Gnomad4 SAS

AF:

0.0598

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.0393

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0405

Hom.:

328

Bravo

AF:

0.0369

TwinsUK

AF:

0.0429

AC:

159

ALSPAC

AF:

0.0444

AC:

171

ESP6500AA

AF:

0.0223

AC:

ESP6500EA

AF:

0.0377

AC:

324

ExAC

AF:

0.0447

AC:

5422

Asia WGS

AF:

0.0950

AC:

331

AN:

3478

EpiCase

AF:

0.0358

EpiControl

AF:

0.0311

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

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

MetaRNN

Benign

0.0036

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.5

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

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.7

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

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.99

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

Vest4

0.36, 0.39, 0.21

MPC

1.2

ClinPred

0.015

GERP RS

3.4

Varity_R

0.83

gMVP

0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over