17-44911779-C-T

Variant names:

• chr17-44911779-C-T
• NM_002055.5:c.799G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002055.5(GFAP):​c.799G>A​(p.Ala267Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,258 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.94

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.799G>A	p.Ala267Thr	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.799G>A	p.Ala267Thr	missense_variant	Exon 5 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461258 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726948

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;D;.;.;.;.;.;D;.
Eigen	Benign	0.083
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.99	.;L;.;.;L;L;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	.;.;N;.;N;.;.;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.017	.;.;D;.;D;.;.;.;.
Sift4G	Uncertain	0.035	.;.;D;.;D;.;D;.;.
Polyphen		0.90	.;P;.;.;.;.;.;.;.
Vest4		0.44, 0.43, 0.41
MutPred		0.57		Gain of phosphorylation at A267 (P = 0.0277);Gain of phosphorylation at A267 (P = 0.0277);Gain of phosphorylation at A267 (P = 0.0277);.;Gain of phosphorylation at A267 (P = 0.0277);Gain of phosphorylation at A267 (P = 0.0277);Gain of phosphorylation at A267 (P = 0.0277);.;.;
MVP		1.0
MPC		0.55
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.37
gMVP		0.82

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.

Other links and lift over

hg19: chr17-42989147;