Variant rs763868966 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PVS1BS1_Supporting

The NM_002055.5(GFAP):c.934G>T(p.Glu312Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000168 in 1,610,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E312E) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

GFAP
NM_002055.5 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 6.13

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 Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000178 (26/1458684) while in subpopulation EAS AF= 0.000605 (24/39682). AF 95% confidence interval is 0.000416. There are 0 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GFAP	NM_002055.5 linkuse as main transcript	c.934G>T	p.Glu312Ter	stop_gained	6/9	ENST00000588735.3
GFAP	NM_001363846.2 linkuse as main transcript	c.934G>T	p.Glu312Ter	stop_gained	6/10
GFAP	NM_001242376.3 linkuse as main transcript	c.934G>T	p.Glu312Ter	stop_gained	6/7
GFAP	NM_001131019.3 linkuse as main transcript	c.934G>T	p.Glu312Ter	stop_gained	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3 linkuse as main transcript	c.934G>T	p.Glu312Ter	stop_gained	6/9	1	NM_002055.5	P1	P14136-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248618

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134602

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1458684

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

725488

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000605

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Alexander disease

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.62

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

A;A;A;D

Vest4

0.94, 0.94

GERP RS

4.7

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

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