rs78994946

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001363846.2(GFAP):c.1288C>T(p.Arg430Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,613,924 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 54 hom., cov: 31)

Exomes 𝑓: 0.027 ( 611 hom. )

Consequence

GFAP
NM_001363846.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 2.96

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=0.0070183575).

BP6

Variant 17-44910144-G-A is Benign according to our data. Variant chr17-44910144-G-A is described in ClinVar as [Benign]. Clinvar id is 66449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44910144-G-A is described in Lovd as [Likely_benign]. Variant chr17-44910144-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3235/152298) while in subpopulation NFE AF= 0.0298 (2030/68038). AF 95% confidence interval is 0.0288. There are 54 homozygotes in gnomad4. There are 1544 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3235 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.1171+471C>T		intron_variant	Intron 7 of 8	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.1288C>T	p.Arg430Cys	missense_variant	Exon 8 of 10		NP_001350775.1
GFAP	NM_001131019.3 link	c.1288C>T	p.Arg430Cys	missense_variant	Exon 8 of 8		NP_001124491.1	P14136-3
GFAP	NM_001242376.3 link	c.*325C>T		3_prime_UTR_variant	Exon 7 of 7		NP_001229305.1	P14136-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.1171+471C>T		intron_variant	Intron 7 of 8	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3233

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00519

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0222

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0358

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0227

AC:

5652

AN:

248848

Hom.:

AF XY:

0.0231

AC XY:

3129

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.00531

Gnomad AMR exome

AF:

0.0136

Gnomad ASJ exome

AF:

0.0295

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0164

Gnomad FIN exome

AF:

0.0366

Gnomad NFE exome

AF:

0.0299

Gnomad OTH exome

AF:

0.0241

GnomAD4 exome

AF:

0.0269

AC:

39335

AN:

1461626

Hom.:

611

Cov.:

AF XY:

0.0269

AC XY:

19558

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.0152

Gnomad4 ASJ exome

AF:

0.0303

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0171

Gnomad4 FIN exome

AF:

0.0360

Gnomad4 NFE exome

AF:

0.0294

Gnomad4 OTH exome

AF:

0.0251

GnomAD4 genome

AF:

0.0212

AC:

3235

AN:

152298

Hom.:

Cov.:

AF XY:

0.0207

AC XY:

1544

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00517

Gnomad4 AMR

AF:

0.0222

Gnomad4 ASJ

AF:

0.0305

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0149

Gnomad4 FIN

AF:

0.0358

Gnomad4 NFE

AF:

0.0298

Gnomad4 OTH

AF:

0.0302

Alfa

AF:

0.0265

Hom.:

Bravo

AF:

0.0197

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0234

AC:

ESP6500AA

AF:

0.00606

AC:

ESP6500EA

AF:

0.0318

AC:

228

ExAC

AF:

0.0233

AC:

2806

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0301

EpiControl

AF:

0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jun 29, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.51

T;T

MetaRNN

Benign

0.0065

T;T

MetaSVM

Benign

-0.70

PROVEAN

Uncertain

-2.4

.;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.015

.;D

Vest4

0.039

ClinPred

0.040

GERP RS

3.8

gMVP

0.50

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