rs797044592

Variant names:

• chr17-44910133-CAGCTAAC-GAT
• rs797044592
• NM_002055.5:c.1171+475_1171+482delGTTAGCTGinsATC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001363846.2(GFAP):​c.1291+1_1291+8delGTTAGCTGinsATC variant causes a splice donor, splice region, intron 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GFAP NM_001363846.2 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.52
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08456659 fraction of the gene. Cryptic splice site detected, with MaxEntScore 2.5, offset of 49, new splice context is: ggaGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44910133-CAGCTAAC-GAT is Pathogenic according to our data. Variant chr17-44910133-CAGCTAAC-GAT is described in ClinVar as Pathogenic. ClinVar VariationId is 190366.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363846.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.1171+475_1171+482delGTTAGCTGinsATC		intron	N/A	NP_002046.1	P14136-1
	GFAP	NM_001131019.3		c.1292_*3delGTTAGCTGinsATC	p.Gly431fs	frameshift stop_lost synonymous	Exon 8 of 8	NP_001124491.1	P14136-3
	GFAP	NM_001242376.3		c.*329_*336delGTTAGCTGinsATC		3_prime_UTR	Exon 7 of 7	NP_001229305.1	P14136-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.1171+475_1171+482delGTTAGCTGinsATC		intron	N/A	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.2800_2807delGTTAGCTGinsATC		non_coding_transcript_exon	Exon 5 of 5
	GFAP	ENST00000585543.6	TSL:1	n.324+475_324+482delGTTAGCTGinsATC		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Alexander disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5

Splicing

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

Other links and lift over

dbSNP: rs797044592; hg19: chr17-42987501;