rs2276625

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001371279.1(REEP1):c.285G>A(p.Thr95Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,610,440 control chromosomes in the GnomAD database, including 163,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13073 hom., cov: 33)

Exomes 𝑓: 0.45 ( 150171 hom. )

Consequence

REEP1
NM_001371279.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -3.15

Publications

29 publications found

Variant links:

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]

REEP1 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 31
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
neuronopathy, distal hereditary motor, type 5B
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
neuronopathy, distal hereditary motor, type 5A
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spinal muscular atrophy, distal, autosomal recessive, 6
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

REEP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 2-86254712-C-T is Benign according to our data. Variant chr2-86254712-C-T is described in ClinVar as Benign. ClinVar VariationId is 130108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP1	NM_001371279.1 link	c.285G>A	p.Thr95Thr	synonymous_variant	Exon 4 of 9	ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924.7 link	c.285G>A	p.Thr95Thr	synonymous_variant	Exon 4 of 9	5	NM_001371279.1	ENSP00000438346.3		A0A1C7CYY3

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60496

AN:

151990

Hom.:

13051

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.502

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.589

Gnomad SAS

AF:

0.453

Gnomad FIN

AF:

0.506

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.445

Gnomad OTH

AF:

0.430

GnomAD2 exomes

AF:

0.475

AC:

119360

AN:

251322

AF XY:

0.474

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.619

Gnomad ASJ exome

AF:

0.452

Gnomad EAS exome

AF:

0.607

Gnomad FIN exome

AF:

0.496

Gnomad NFE exome

AF:

0.450

Gnomad OTH exome

AF:

0.478

GnomAD4 exome

AF:

0.449

AC:

655097

AN:

1458332

Hom.:

150171

Cov.:

AF XY:

0.449

AC XY:

325952

AN XY:

725598

show subpopulations

African (AFR)

AF:

0.211

AC:

7041

AN:

33428

American (AMR)

AF:

0.607

AC:

27123

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.450

AC:

11735

AN:

26096

East Asian (EAS)

AF:

0.593

AC:

23514

AN:

39676

South Asian (SAS)

AF:

0.454

AC:

39096

AN:

86178

European-Finnish (FIN)

AF:

0.496

AC:

26478

AN:

53364

Middle Eastern (MID)

AF:

0.439

AC:

2532

AN:

5764

European-Non Finnish (NFE)

AF:

0.443

AC:

491045

AN:

1108804

Other (OTH)

AF:

0.440

AC:

26533

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

17814

35629

53443

71258

89072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14844

29688

44532

59376

74220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.398

AC:

60545

AN:

152108

Hom.:

13073

Cov.:

AF XY:

0.405

AC XY:

30105

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.222

AC:

9223

AN:

41502

American (AMR)

AF:

0.503

AC:

7689

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1580

AN:

3470

East Asian (EAS)

AF:

0.589

AC:

3046

AN:

5168

South Asian (SAS)

AF:

0.454

AC:

2188

AN:

4824

European-Finnish (FIN)

AF:

0.506

AC:

5351

AN:

10578

Middle Eastern (MID)

AF:

0.428

AC:

125

AN:

292

European-Non Finnish (NFE)

AF:

0.445

AC:

30234

AN:

67972

Other (OTH)

AF:

0.427

AC:

901

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1818

3637

5455

7274

9092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

588

1176

1764

2352

2940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.435

Hom.:

24431

Bravo

AF:

0.395

Asia WGS

AF:

0.496

AC:

1724

AN:

3478

EpiCase

AF:

0.443

EpiControl

AF:

0.451

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 16, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 31

Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 15, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronopathy, distal hereditary motor, type 5B

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.0

(source)

DANN

Benign

0.39

PhyloP100

-3.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over