rs201382676

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_002055.5(GFAP):c.848A>G(p.Asn283Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.34

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: 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14081389).

BP6

Variant 17-44911730-T-C is Benign according to our data. Variant chr17-44911730-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 323613.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000722 (11/152340) while in subpopulation NFE AF = 0.000118 (8/68008). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.848A>G	p.Asn283Ser	missense_variant	Exon 5 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.848A>G	p.Asn283Ser	missense_variant	Exon 5 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.848A>G	p.Asn283Ser	missense_variant	Exon 5 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.848A>G	p.Asn283Ser	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.848A>G	p.Asn283Ser	missense_variant	Exon 5 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000962

AC:

AN:

249566

AF XY:

0.0000814

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

226

AN:

1461684

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000195

AC:

217

AN:

1111970

Other (OTH)

AF:

0.0000994

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

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:

0.0000722

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41592

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000165

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 283 of the GFAP protein (p.Asn283Ser). This variant is present in population databases (rs201382676, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GFAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 323613). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Nov 24, 2020

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GFAP-related disorder

Benign:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.71

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

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.066

MetaRNN

Benign

0.14

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

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

0.81

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

PhyloP100

1.3

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.43

Sift

Benign

0.34

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

Sift4G

Benign

0.59

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

Polyphen

0.18

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

Vest4

0.17, 0.17, 0.19

MVP

1.0

MPC

0.37

ClinPred

0.052

GERP RS

4.4

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.49

gMVP

0.84

Mutation Taster

=26/74

disease causing

(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