rs267607513

chr17-44911375-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002055.5(GFAP):c.988C>G(p.Arg330Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R330P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.85

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.

• PM1: In a region_of_interest Coil 2B (size 120) in uniprot entity GFAP_HUMAN there are 26 pathogenic changes around while only 6 benign (81%) in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.988C>G	p.Arg330Gly	missense_variant	6/9	ENST00000588735.3
GFAP	NM_001363846.2	c.988C>G	p.Arg330Gly	missense_variant	6/10
GFAP	NM_001242376.3	c.988C>G	p.Arg330Gly	missense_variant	6/7
GFAP	NM_001131019.3	c.988C>G	p.Arg330Gly	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.988C>G	p.Arg330Gly	missense_variant	6/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T;T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.45	T
Polyphen		0.62	.;P;.;.;.;.
Vest4		0.71, 0.71
MutPred		0.61		Loss of stability (P = 0.0665);Loss of stability (P = 0.0665);Loss of stability (P = 0.0665);.;Loss of stability (P = 0.0665);Loss of stability (P = 0.0665);
MVP		0.98
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.61
gMVP		0.96

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: rs267607513; hg19: chr17-42988743;