NM_002055.5:c.992T>G

Variant names:

• chr17-44911371-A-C
• NM_002055.5:c.992T>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.992T>G​(p.Leu331Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 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.

• 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: 9.32

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, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.992T>G	p.Leu331Arg	missense_variant	Exon 6 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.992T>G	p.Leu331Arg	missense_variant	Exon 6 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.992T>G	p.Leu331Arg	missense_variant	Exon 6 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.992T>G	p.Leu331Arg	missense_variant	Exon 6 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.992T>G	p.Leu331Arg	missense_variant	Exon 6 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727196

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	0.24
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T;T;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	.;M;.;.;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	.;.;D;.;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	.;.;D;.;D;.
Sift4G	Pathogenic	0.0	.;.;D;.;D;.
Polyphen		0.98	.;D;.;.;.;.
Vest4		0.94, 0.94
MutPred		0.76		Loss of stability (P = 0.0576);Loss of stability (P = 0.0576);Loss of stability (P = 0.0576);.;Loss of stability (P = 0.0576);Loss of stability (P = 0.0576);
MVP		1.0
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: chr17-42988739;