chr2-86251959-T-A

Position:

• chr2-86251959-T-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_001371279.1(REEP1):​c.415A>T​(p.Lys139Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: REEP1 NM_001371279.1 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.90

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 13 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-86251959-T-A is Pathogenic according to our data. Variant chr2-86251959-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 188118.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.415A>T	p.Lys139Ter	stop_gained, splice_region_variant	5/9	ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924.7	c.415A>T	p.Lys139Ter	stop_gained, splice_region_variant	5/9	5	NM_001371279.1	ENSP00000438346

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 31 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 02, 2014

Truncating sequence changes of REEP1 are known to be pathogenic. This sequence change has not been published in the literature and is not present in population databases. This sequence change creates a premature translational stop signal at codon 139 (p.Lys139*). It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A;A;A;D
Vest4		0.92
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.010		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: rs786204081; hg19: chr2-86479082;