Variant chr17-44910632-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The ENST00000588735.3(GFAP):c.1154C>T(p.Ser385Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S385C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GFAP
ENST00000588735.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 9.34

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a region_of_interest Tail (size 54) in uniprot entity GFAP_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in ENST00000588735.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-44910632-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GFAP	NM_002055.5 linkuse as main transcript	c.1154C>T	p.Ser385Phe	missense_variant	7/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2 linkuse as main transcript	c.1154C>T	p.Ser385Phe	missense_variant	7/10		NP_001350775.1
GFAP	NM_001242376.3 linkuse as main transcript	c.1154C>T	p.Ser385Phe	missense_variant	7/7		NP_001229305.1
GFAP	NM_001131019.3 linkuse as main transcript	c.1154C>T	p.Ser385Phe	missense_variant	7/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 linkuse as main transcript	c.1154C>T	p.Ser385Phe	missense_variant	7/9	1	NM_002055.5	ENSP00000466598	P1	P14136-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1432106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709080

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Alexander disease

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;D;.;.;.;.;.;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

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

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.85

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

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

2.9

.;M;.;.;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.14

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

Vest4

0.82, 0.82

MutPred

0.52

Loss of disorder (P = 0.0409);Loss of disorder (P = 0.0409);Loss of disorder (P = 0.0409);.;.;Loss of disorder (P = 0.0409);Loss of disorder (P = 0.0409);.;

MVP

1.0

ClinPred

0.99

GERP RS

5.1

Varity_R

0.63

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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