rs387906263

chr2-86232707-TG-Tchr2-86232707-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001371279.1(REEP1):c.512del(p.Pro171HisfsTer46) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,458,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: REEP1 NM_001371279.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.59

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-86232707-TG-T is Pathogenic according to our data. Variant chr2-86232707-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-86232707-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REEP1	NM_001371279.1	c.512del	p.Pro171HisfsTer46	frameshift_variant	6/9	ENST00000538924.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REEP1	ENST00000538924.7	c.512del	p.Pro171HisfsTer46	frameshift_variant	6/9	5	NM_001371279.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458782 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 31 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	May 17, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2022	For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the REEP1 protein. Other variant(s) that result in a similarly extended protein product (p.Pro172Hisfs*51) have been determined to be pathogenic (Invitae). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1859). This variant is also known as c.507delC. This frameshift has been observed in individual(s) with hereditary spastic paraplegia (PMID: 16826527, 30637453). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the REEP1 gene (p.Pro171Hisfs*52). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the REEP1 protein and extend the protein by 20 additional amino acid residues. -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906263; hg19: chr2-86459830;