rs797044575

Variant names:

• chr17-44915113-A-AGCCGCAGCT
• rs797044575
• NM_002055.5:c.365_373dupAGCTGCGGC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_002055.5(GFAP):​c.365_373dupAGCTGCGGC​(p.Arg124_Leu125insGlnLeuArg) variant causes a conservative 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 conservative_inframe_insertion
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.33
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Alexander disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 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 rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.365_373dupAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	conservative_inframe_insertion	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.365_373dupAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	conservative_inframe_insertion	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.365_373dupAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	conservative_inframe_insertion	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.365_373dupAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	conservative_inframe_insertion	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.365_373dupAGCTGCGGC	p.Arg124_Leu125insGlnLeuArg	conservative_inframe_insertion	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=56/44	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs797044575; hg19: chr17-42992481;