rs797044576

Variant names:

• chr17-44915106-G-GAGCCGC
• rs797044576
• NM_002055.5:c.375_380dupGCGGCT

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.375_380dupGCGGCT​(p.Leu127_Asp128insArgLeu) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. L127L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 disruptive_inframe_insertion
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.31
• Publications: 0 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, 8 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.375_380dupGCGGCT	p.Leu127_Asp128insArgLeu	disruptive_inframe_insertion	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.375_380dupGCGGCT	p.Leu127_Asp128insArgLeu	disruptive_inframe_insertion	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.375_380dupGCGGCT	p.Leu127_Asp128insArgLeu	disruptive_inframe_insertion	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.375_380dupGCGGCT	p.Leu127_Asp128insArgLeu	disruptive_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.375_380dupGCGGCT	p.Leu127_Asp128insArgLeu	disruptive_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		5.3
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs797044576; hg19: chr17-42992474;