rs773482099

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BS1_SupportingBS2

The NM_002055.5(GFAP):c.265T>C(p.Phe89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.84

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_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_002055.5

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000985 (15/152212) while in subpopulation AMR AF= 0.000851 (13/15280). AF 95% confidence interval is 0.000503. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GFAP	NM_002055.5 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	1/9	ENST00000588735.3
GFAP	NM_001363846.2 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	1/10
GFAP	NM_001242376.3 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	1/7
GFAP	NM_001131019.3 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	1/9	1	NM_002055.5	P1	P14136-1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000955

Bravo

AF:

0.000128

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 10, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 585932). This variant has not been reported in the literature in individuals affected with GFAP-related conditions. This variant is present in population databases (rs773482099, gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the GFAP protein (p.Phe89Leu). -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.265T>C (p.F89L) alteration is located in exon 1 (coding exon 1) of the GFAP gene. This alteration results from a T to C substitution at nucleotide position 265, causing the phenylalanine (F) at amino acid position 89 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.014

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.82

T;T;T;T;T;D;D;D;D

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.52

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

MetaSVM

Uncertain

0.35

MutationTaster

Benign

0.62

D;D;D;D

PrimateAI

Uncertain

0.67

Polyphen

0.056

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

Vest4

0.15, 0.19, 0.18

MutPred

0.57

Gain of catalytic residue at F89 (P = 0.0187);Gain of catalytic residue at F89 (P = 0.0187);Gain of catalytic residue at F89 (P = 0.0187);Gain of catalytic residue at F89 (P = 0.0187);Gain of catalytic residue at F89 (P = 0.0187);Gain of catalytic residue at F89 (P = 0.0187);Gain of catalytic residue at F89 (P = 0.0187);Gain of catalytic residue at F89 (P = 0.0187);Gain of catalytic residue at F89 (P = 0.0187);

MVP

0.98

MPC

0.47

ClinPred

0.43

GERP RS

4.7

Varity_R

0.34

gMVP

0.74

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

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