rs56679084

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_002055.5(GFAP):c.667G>C(p.Glu223Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,614,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E223V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3O:1

Conservation

PhyloP100: 7.91

Publications

14 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3495084).

BP6

Variant 17-44913382-C-G is Benign according to our data. Variant chr17-44913382-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 66494.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000276 (42/152338) while in subpopulation NFE AF = 0.0005 (34/68032). AF 95% confidence interval is 0.000367. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.667G>C	p.Glu223Gln	missense_variant	Exon 4 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.667G>C	p.Glu223Gln	missense_variant	Exon 4 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.667G>C	p.Glu223Gln	missense_variant	Exon 4 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.667G>C	p.Glu223Gln	missense_variant	Exon 4 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.667G>C	p.Glu223Gln	missense_variant	Exon 4 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000346

AC:

AN:

251394

AF XY:

0.000339

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000248

AC:

362

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

184

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000402

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000359

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000246

AC:

274

AN:

1111996

Other (OTH)

AF:

0.000298

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000276

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.000196

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68032

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000366

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alexander disease

Pathogenic:1Uncertain:2Benign:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of Alexander disease (MIM#203450). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP2,PM1,PP5. -

Jan 08, 2015

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1Benign:2Other:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GFAP: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.35

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

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.4

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

PhyloP100

7.9

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.3

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

REVEL

Pathogenic

0.69

Sift

Benign

0.061

.;.;T;.;T;.;.;.

Sift4G

Benign

0.081

.;.;T;.;T;.;T;.

Polyphen

0.93

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

Vest4

0.59, 0.59, 0.57

MVP

1.0

MPC

1.2

ClinPred

0.15

GERP RS

4.9

Varity_R

0.44

gMVP

0.57

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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