Genetic Variant NM_002055.5:c.187A>C (chr17-44915300-T-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_002055.5(GFAP):c.187A>C(p.Lys63Gln) variant causes a missense change involving the alteration of a non-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).

Frequency

Genomes: not found (cov: 32)

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

not provided no classification provided O:2

Conservation

PhyloP100: 1.15

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Alexander disease
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
Alexander disease type II
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GFAP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002055.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.187A>C	p.Lys63Gln	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.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:2

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Alexander disease

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.46

.;T;.;.;.;T;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

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

M_CAP

Benign

0.073

MetaRNN

Pathogenic

0.80

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

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.6

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

PhyloP100

1.1

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.5

.;.;N;N;.;.;.;.;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.023

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

Sift4G

Benign

0.15

.;.;T;T;.;T;T;.;.

Polyphen

0.37

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

Vest4

0.61, 0.64, 0.75

MutPred

0.83

Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);

MVP

0.96

MPC

0.98

ClinPred

0.88

GERP RS

3.7

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.81

gMVP

0.88

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over