rs377637314

chr2-86217057-C-Achr2-86217057-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP7 BS1

The NM_001371279.1(REEP1):c.837G>T(p.Ser279=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00077 in 1,613,806 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (2 hom.)
• Consequence: REEP1 NM_001371279.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:8
• Conservation: PhyloP100: 0.0270

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000658 (100/151990) while in subpopulation NFE AF= 0.00132 (90/67990). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REEP1	NM_001371279.1	c.837G>T	p.Ser279=	synonymous_variant	9/9	ENST00000538924.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REEP1	ENST00000538924.7	c.837G>T	p.Ser279=	synonymous_variant	9/9	5	NM_001371279.1

Frequencies

GnomAD3 genomes AF: 0.000658 AC: 100 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000783 AC: 195 AN: 249088 Hom.: 0 AF XY: 0.000853 AC XY: 115 AN XY: 134828

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000947

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000781 AC: 1142 AN: 1461816 Hom.: 2 Cov.: 30 AF XY: 0.000821 AC XY: 597 AN XY: 727216

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.000867

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000658 AC: 100 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.000539 AC XY: 40 AN XY: 74220

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000573 Hom.: 0

Bravo AF: 0.000544

EpiCase AF: 0.00109

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 31 Pathogenic:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2021	This variant is associated with the following publications: (PMID: 19034539, 18644145, 26671083, 20718791, 18321925, 19290790, 16826527) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	REEP1: BP4, BP7 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 25, 2019

The REEP1 c.*43G>T variant (rs377637314), also known as c.606+43G>T, is reported in the literature in multiple individuals affected with spastic paraplegia, many of whom also had a family history of disease (Beetz 2008, Elert-Dobkowska 2015, Hewamadduma 2009, Schlang 2008, Zuchner 2006). This variant has been observed in at least one unaffected relative of an affected individual, although no neurological examination of the unaffected individual was performed (Beetz 2008). The c.*43G>T variant is found in the non-Finnish European population with an overall allele frequency of 0.14% (180/126816 alleles) in the Genome Aggregation Database. This variant occurs in the 3' untranslated region at a nucleotide that is moderately conserved and is predicted to alter a microRNA binding site and impact protein levels (Zuchner 2006), although functional studies would be required to confirm this. In an alternative transcript, NM_001164732.1, this is a synonymous variant, but computational analyses (Alamut v.2.11) predict that it does not alter splicing. Given the lack of clinical and functional data, the significance of the c.*43G>T variant is uncertain at this time. References: Beetz C et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008 Apr;131(Pt 4):1078-86. Elert-Dobkowska E et al. Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients. J Neurol Sci. 2015 Dec 15;359(1-2):35-9. Hewamadduma C et al. New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). Neurogenetics. 2009 Apr;10(2):105-10. Schlang KJ et al. Autosomal dominant hereditary spastic paraplegia: novel mutations in the REEP1 gene (SPG31). BMC Med Genet. 2008 Jul 21;9:71. Zuchner S et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet. 2006 Aug;79(2):365-9. -

Neuronopathy, distal hereditary motor, type 5B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 01, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

REEP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	5.8
Dann	Benign	0.88

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: rs377637314; hg19: chr2-86444180;