rs121918262

Positions:

• chr2-86282216-G-A
• chr2-86282216-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM5 PP3_Moderate PP5_Moderate

The NM_001371279.1(REEP1):​c.59C>T​(p.Ala20Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,456,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A20E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: REEP1 NM_001371279.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.97

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001371279.1
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-86282216-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 2-86282216-G-A is Pathogenic according to our data. Variant chr2-86282216-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 943302.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REEP1	NM_001371279.1	c.59C>T	p.Ala20Val	missense_variant	2/9	ENST00000538924.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REEP1	ENST00000538924.7	c.59C>T	p.Ala20Val	missense_variant	2/9	5	NM_001371279.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251388 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1456730 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 31 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala20 amino acid residue in REEP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16826527, 18321925, 20718791, 23812641). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt REEP1 protein function. ClinVar contains an entry for this variant (Variation ID: 943302). This variant has not been reported in the literature in individuals affected with REEP1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 20 of the REEP1 protein (p.Ala20Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.9	M;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.9	D;.;.;.;.;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;.;.;.;.;.;D
Sift4G	Uncertain	0.0020	D;.;.;.;.;D;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.88
MutPred		0.67		Gain of methylation at K25 (P = 0.0909);.;.;Gain of methylation at K25 (P = 0.0909);.;Gain of methylation at K25 (P = 0.0909);.;
MVP		0.92
MPC		1.9
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.67
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs121918262; hg19: chr2-86509339; COSMIC: COSV51256355; COSMIC: COSV51256355;