rs797044583

Variant names:

• chr17-44911710-G-C
• rs797044583
• NM_002055.5:c.868C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002055.5(GFAP):​c.868C>G​(p.Gln290Glu) 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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.868C>G	p.Gln290Glu	missense_variant	Exon 5 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.868C>G	p.Gln290Glu	missense_variant	Exon 5 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.868C>G	p.Gln290Glu	missense_variant	Exon 5 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.868C>G	p.Gln290Glu	missense_variant	Exon 5 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.868C>G	p.Gln290Glu	missense_variant	Exon 5 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Alexander disease Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	2.9	.;M;.;.;M;M;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	.;.;D;.;D;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	.;.;D;.;D;.;.;.;.
Sift4G	Uncertain	0.0030	.;.;D;.;D;.;D;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.89, 0.93
MutPred		0.73		Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);.;Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);.;.;
MVP		1.0
MPC		1.3
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.90
gMVP		0.98

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

Other links and lift over

dbSNP: rs797044583; hg19: chr17-42989078;