NM_002055.5:c.140C>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.140C>T(p.Pro47Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,612,262 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P47P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0053 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 45 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 2.09

Publications

13 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=0.006749183).

BP6

Variant 17-44915347-G-A is Benign according to our data. Variant chr17-44915347-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 66457.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 = 0.00532 (810/152348) while in subpopulation NFE AF = 0.00955 (650/68040). AF 95% confidence interval is 0.00894. There are 2 homozygotes in GnomAd4. There are 376 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 810 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GFAP	NM_002055.5 link	c.140C>T	p.Pro47Leu	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2 link	c.140C>T	p.Pro47Leu	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.140C>T	p.Pro47Leu	missense_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3 link	c.140C>T	p.Pro47Leu	missense_variant	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.140C>T	p.Pro47Leu	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes

AF:

0.00532

AC:

810

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00955

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00493

AC:

1230

AN:

249678

AF XY:

0.00484

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.00307

Gnomad ASJ exome

AF:

0.00838

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00334

Gnomad NFE exome

AF:

0.00781

Gnomad OTH exome

AF:

0.00393

GnomAD4 exome

AF:

0.00697

AC:

10180

AN:

1459914

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

4934

AN XY:

725886

show subpopulations

African (AFR)

AF:

0.000837

AC:

AN:

33464

American (AMR)

AF:

0.00293

AC:

131

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00796

AC:

208

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39666

South Asian (SAS)

AF:

0.00145

AC:

125

AN:

86226

European-Finnish (FIN)

AF:

0.00305

AC:

162

AN:

53096

Middle Eastern (MID)

AF:

0.00244

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00821

AC:

9114

AN:

1110616

Other (OTH)

AF:

0.00658

AC:

397

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

564

1128

1691

2255

2819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.00532

AC:

810

AN:

152348

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

376

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41566

American (AMR)

AF:

0.00268

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00955

AC:

650

AN:

68040

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00696

Hom.:

Bravo

AF:

0.00470

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00502

AC:

609

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6Other:1

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 08, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GFAP: BS2 -

Dec 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 29, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 14, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Alexander disease

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.29

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

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.92

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

MetaRNN

Benign

0.0067

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

MetaSVM

Benign

-0.52

MutationAssessor

Benign

2.0

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

PhyloP100

2.1

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.61

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

REVEL

Uncertain

0.49

Sift

Benign

0.34

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

Sift4G

Benign

0.17

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

Polyphen

0.021

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

Vest4

0.39, 0.41

MVP

0.95

MPC

0.60

ClinPred

0.019

GERP RS

4.8

PromoterAI

-0.0068

Neutral

(source)

Varity_R

0.19

gMVP

0.70

Mutation Taster

=99/1

polymorphism

(source)

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

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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