rs267607523

Positions:

• chr17-44915273-C-G
• chr17-44915273-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002055.5(GFAP):​c.214G>C​(p.Glu72Gln) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.79

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35726166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.214G>C	p.Glu72Gln	missense_variant	1/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.214G>C	p.Glu72Gln	missense_variant	1/10		NP_001350775.1
GFAP	NM_001242376.3	c.214G>C	p.Glu72Gln	missense_variant	1/7		NP_001229305.1
GFAP	NM_001131019.3	c.214G>C	p.Glu72Gln	missense_variant	1/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.214G>C	p.Glu72Gln	missense_variant	1/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.81
DEOGEN2	Uncertain	0.58	.;D;.;.;.;T;.;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.67	.;N;.;N;N;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	.;.;N;N;.;.;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.52	.;.;T;T;.;.;.;.;.
Sift4G	Benign	0.81	.;.;T;T;.;T;T;.;.
Polyphen		0.23	.;B;.;.;.;.;.;.;.
Vest4		0.26, 0.27, 0.27
MutPred		0.66		Gain of MoRF binding (P = 0.0442);Gain of MoRF binding (P = 0.0442);Gain of MoRF binding (P = 0.0442);Gain of MoRF binding (P = 0.0442);Gain of MoRF binding (P = 0.0442);Gain of MoRF binding (P = 0.0442);Gain of MoRF binding (P = 0.0442);Gain of MoRF binding (P = 0.0442);Gain of MoRF binding (P = 0.0442);
MVP		0.99
MPC		0.45
ClinPred		0.41	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.89

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: rs267607523; hg19: chr17-42992641;