dbSNP rs147282497: GFAP:p.Thr110Ile (chr17-44915158-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002055.5(GFAP):c.329C>T(p.Thr110Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T110S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.31

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.329C>T	p.Thr110Ile	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.329C>T	p.Thr110Ile	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.329C>T	p.Thr110Ile	missense_variant	Exon 1 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.329C>T	p.Thr110Ile	missense_variant	Exon 1 of 8		NP_001124491.1	P14136-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.329C>T	p.Thr110Ile	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

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

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.76

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

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.9

.;L;.;L;L;.;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.3

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

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0040

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

Polyphen

0.87

.;P;.;.;.;.;.;.;.

Vest4

0.27, 0.45, 0.30

MutPred

0.43

Loss of disorder (P = 0.0401);Loss of disorder (P = 0.0401);Loss of disorder (P = 0.0401);Loss of disorder (P = 0.0401);Loss of disorder (P = 0.0401);Loss of disorder (P = 0.0401);Loss of disorder (P = 0.0401);Loss of disorder (P = 0.0401);Loss of disorder (P = 0.0401);

MVP

1.0

MPC

1.1

ClinPred

0.99

GERP RS

4.7

Varity_R

0.75

gMVP

0.56

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over