17-44914081-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002055.5(GFAP):c.469G>A(p.Asp157Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0165 in 1,549,378 control chromosomes in the GnomAD database, including 282 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 32)

Exomes 𝑓: 0.017 ( 266 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 3.80

Publications

20 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0133288205).

BP6

Variant 17-44914081-C-T is Benign according to our data. Variant chr17-44914081-C-T is described in ClinVar as Benign. ClinVar VariationId is 66485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1658/152104) while in subpopulation NFE AF = 0.0173 (1179/67984). AF 95% confidence interval is 0.0165. There are 16 homozygotes in GnomAd4. There are 789 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1658 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GFAP	NM_002055.5 link	c.469G>A	p.Asp157Asn	missense_variant	Exon 2 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2 link	c.469G>A	p.Asp157Asn	missense_variant	Exon 2 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.469G>A	p.Asp157Asn	missense_variant	Exon 2 of 7		NP_001229305.1
GFAP	NM_001131019.3 link	c.469G>A	p.Asp157Asn	missense_variant	Exon 2 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.469G>A	p.Asp157Asn	missense_variant	Exon 2 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1657

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00310

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00583

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0109

AC:

1746

AN:

159742

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.00330

Gnomad AMR exome

AF:

0.00493

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0189

Gnomad OTH exome

AF:

0.00918

GnomAD4 exome

AF:

0.0171

AC:

23837

AN:

1397274

Hom.:

266

Cov.:

AF XY:

0.0166

AC XY:

11443

AN XY:

689466

show subpopulations

African (AFR)

AF:

0.00296

AC:

AN:

31708

American (AMR)

AF:

0.00494

AC:

177

AN:

35850

Ashkenazi Jewish (ASJ)

AF:

0.00909

AC:

228

AN:

25080

East Asian (EAS)

AF:

0.00

AC:

AN:

35976

South Asian (SAS)

AF:

0.00101

AC:

AN:

79362

European-Finnish (FIN)

AF:

0.0165

AC:

805

AN:

48760

Middle Eastern (MID)

AF:

0.00447

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.0201

AC:

21686

AN:

1077092

Other (OTH)

AF:

0.0128

AC:

742

AN:

57850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1033

2066

3099

4132

5165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

832

1664

2496

3328

4160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0109

AC:

1658

AN:

152104

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

789

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00309

AC:

128

AN:

41476

American (AMR)

AF:

0.00582

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00125

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0182

AC:

193

AN:

10576

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0173

AC:

1179

AN:

67984

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0164

Hom.:

Bravo

AF:

0.0107

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00620

AC:

ESP6500EA

AF:

0.0142

AC:

121

ExAC

AF:

0.00690

AC:

741

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GFAP: BP4, BS1, BS2 -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 25, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

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

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

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

MetaRNN

Benign

0.013

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

MetaSVM

Uncertain

-0.080

MutationAssessor

Benign

1.2

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

PhyloP100

3.8

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

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

REVEL

Uncertain

0.37

Sift

Uncertain

0.025

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

Sift4G

Uncertain

0.024

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

Polyphen

0.0040

.;B;.;.;.;.;.;.;.;.

Vest4

0.26, 0.27, 0.28

MPC

0.78

ClinPred

0.020

GERP RS

4.6

Varity_R

0.35

gMVP

0.32

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over