rs869320621

Positions:

• chr2-86254686-TATATTAC-TGT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001371279.1(REEP1):​c.303+1_303+7delinsAC variant causes a splice donor, splice donor 5th base, intron 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: REEP1 NM_001371279.1 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.23

Genes affected

REEP1 (HGNC:25786): (receptor accessory protein 1) This gene encodes a mitochondrial protein that functions to enhance the cell surface expression of odorant receptors. Mutations in this gene cause spastic paraplegia autosomal dominant type 31, a neurodegenerative disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of 38, new splice context is: caaGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-86254687-ATATTAC-GT is Pathogenic according to our data. Variant chr2-86254687-ATATTAC-GT is described in ClinVar as [Pathogenic]. Clinvar id is 217864.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.303+1_303+7delinsAC		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924.7	c.303+1_303+7delinsAC		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		5	NM_001371279.1	ENSP00000438346

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spinal muscular atrophy, distal, autosomal recessive, 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 17, 2023

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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: rs869320621; hg19: chr2-86481810;