rs797044575

chr17-44915113-A-AGCCGCAGCT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_002055.5(GFAP):c.373_374insAGCTGCGGC(p.Arg124_Leu125insGlnLeuArg) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 inframe_insertion
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.33

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002055.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.373_374insAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	inframe_insertion	1/9	ENST00000588735.3
GFAP	NM_001131019.3	c.373_374insAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	inframe_insertion	1/8
GFAP	NM_001242376.3	c.373_374insAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	inframe_insertion	1/7
GFAP	NM_001363846.2	c.373_374insAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	inframe_insertion	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.373_374insAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	inframe_insertion	1/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Alexander disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797044575; hg19: chr17-42992481;