17-44911786-CA-AG

Position:

• chr17-44911786-CA-AG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1 PM1 PM2

The NM_002055.5(GFAP):​c.791_792delinsCT​(p.Leu264Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.51

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 8 ACMG points.

• PS1: Transcript NM_002055.5 (GFAP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 190346
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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.791_792delinsCT	p.Leu264Pro	missense_variant	5/9	ENST00000588735.3
GFAP	NM_001131019.3	c.791_792delinsCT	p.Leu264Pro	missense_variant	5/8
GFAP	NM_001242376.3	c.791_792delinsCT	p.Leu264Pro	missense_variant	5/7
GFAP	NM_001363846.2	c.791_792delinsCT	p.Leu264Pro	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.791_792delinsCT	p.Leu264Pro	missense_variant	5/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

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: rs797044580; hg19: chr17-42989154;