chr17-44914081-C-T

Position:

chr17-44914081-C-T

Variant summary

Our verdict is Benign. Variant got -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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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=0.0133288205).

BP6

Variant 17-44914081-C-T is Benign according to our data. Variant chr17-44914081-C-T is described in ClinVar as [Benign]. Clinvar id is 66485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44914081-C-T is described in Lovd as [Likely_benign]. Variant chr17-44914081-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1658 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GFAP	NM_002055.5 linkuse as main transcript	c.469G>A	p.Asp157Asn	missense_variant	2/9	ENST00000588735.3
GFAP	NM_001363846.2 linkuse as main transcript	c.469G>A	p.Asp157Asn	missense_variant	2/10
GFAP	NM_001242376.3 linkuse as main transcript	c.469G>A	p.Asp157Asn	missense_variant	2/7
GFAP	NM_001131019.3 linkuse as main transcript	c.469G>A	p.Asp157Asn	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3 linkuse as main transcript	c.469G>A	p.Asp157Asn	missense_variant	2/9	1	NM_002055.5	P1	P14136-1

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

GnomAD3 exomes

AF:

0.0109

AC:

1746

AN:

159742

Hom.:

AF XY:

0.0103

AC XY:

869

AN XY:

84146

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 SAS exome

AF:

0.00113

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

Gnomad4 AFR exome

AF:

0.00296

Gnomad4 AMR exome

AF:

0.00494

Gnomad4 ASJ exome

AF:

0.00909

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.0165

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.0109

AC:

1658

AN:

152104

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

789

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00309

Gnomad4 AMR

AF:

0.00582

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.0182

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0150

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

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GFAP: BP4, BS1, BS2 -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 25, 2021	- -

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

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;.;.;.;.

MutationTaster

Benign

0.92

D;D;D;D

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

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

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