NM_001371279.1:c.10T>G

Variant names:

• chr2-86337501-A-C
• rs863224189
• NM_001371279.1:c.10T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001371279.1(REEP1):​c.10T>G​(p.Trp4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 1,297,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: REEP1 NM_001371279.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.93

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.10T>G	p.Trp4Gly	missense_variant	Exon 1 of 9	ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924.7	c.10T>G	p.Trp4Gly	missense_variant	Exon 1 of 9	5	NM_001371279.1	ENSP00000438346.3

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150314 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000436 AC: 5 AN: 1147504 Hom.: 0 Cov.: 30 AF XY: 0.00000538 AC XY: 3 AN XY: 557588

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: 0.00

Gnomad4 NFE exome AF: 0.00000527

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150314 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73370

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

REEP1-related disorder Uncertain:1

Mar 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The REEP1 c.2T>G variant is predicted to disrupt the translation initiation site (Start loss). This variant was reported in an individual with mental decline, gait anomalies, muscle anomalies, and positive Babinski sign (Case 13, Table 1, Cui et al. 2020. PubMed ID: 32501971). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary spastic paraplegia 31 Uncertain:1

Mar 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 215086). This variant has not been reported in the literature in individuals affected with REEP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 4 of the REEP1 protein (p.Trp4Gly). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Nov 10, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Trp4Gly (TGG>GGG): c.10 T>G in exon 1 of the REEP1 gene (*NM_022912.2) The W4G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 3,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W4G variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in NEUROPATHY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	31
DANN	Benign	0.93
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.39	T
PROVEAN	Benign	3.4	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Vest4		0.39
MutPred		0.50		Loss of stability (P = 0.0576);
MVP		0.12
ClinPred		0.24	T
GERP RS		2.8

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: rs863224189; hg19: chr2-86564624;