17-44910144-G-C

Variant names:

• chr17-44910144-G-C
• NM_002055.5:c.1171+471C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001363846.2(GFAP):​c.1288C>G​(p.Arg430Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign 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. R430C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GFAP NM_001363846.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22516903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1171+471C>G		intron_variant	Intron 7 of 8	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1288C>G	p.Arg430Gly	missense_variant	Exon 8 of 10		NP_001350775.1
GFAP	NM_001131019.3	c.1288C>G	p.Arg430Gly	missense_variant	Exon 8 of 8		NP_001124491.1
GFAP	NM_001242376.3	c.*325C>G		3_prime_UTR_variant	Exon 7 of 7		NP_001229305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1171+471C>G		intron_variant	Intron 7 of 8	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461646 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727108

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.40	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.66	T
PROVEAN	Benign	-1.7	.;N
REVEL	Benign	0.27
Sift	Uncertain	0.0040	.;D
Sift4G	Benign	0.10	.;T
Vest4		0.13
MutPred		0.26		Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);
MVP		0.57
ClinPred		0.32	T
GERP RS		3.8
gMVP		0.52

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: chr17-42987512; COSMIC: COSV53649703; COSMIC: COSV53649703;