2-86232637-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001371279.1(REEP1):​c.583G>A​(p.Ala195Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,612,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A195S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

REEP1
NM_001371279.1 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.66
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1278753).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
REEP1NM_001371279.1 linkc.583G>A p.Ala195Thr missense_variant Exon 6 of 9 ENST00000538924.7 NP_001358208.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
REEP1ENST00000538924.7 linkc.583G>A p.Ala195Thr missense_variant Exon 6 of 9 5 NM_001371279.1 ENSP00000438346.3 A0A1C7CYY3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152222
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000283
AC:
7
AN:
247690
Hom.:
0
AF XY:
0.0000298
AC XY:
4
AN XY:
134434
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000541
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000425
AC:
62
AN:
1460488
Hom.:
0
Cov.:
32
AF XY:
0.0000427
AC XY:
31
AN XY:
726648
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000567
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Aug 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.583G>A (p.A195T) alteration is located in exon 6 (coding exon 6) of the REEP1 gene. This alteration results from a G to A substitution at nucleotide position 583, causing the alanine (A) at amino acid position 195 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 31 Uncertain:1
Sep 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 195 of the REEP1 protein (p.Ala195Thr). This variant is present in population databases (rs757800031, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with REEP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1015146). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.016
T;.;.;.;.;.;.
Eigen
Benign
0.12
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.86
D;T;T;T;T;D;T
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.13
T;T;T;T;T;T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
-0.14
N;.;.;.;.;.;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.29
N;.;.;.;.;N;.
REVEL
Benign
0.28
Sift
Benign
0.59
T;.;.;.;.;T;.
Sift4G
Benign
0.61
T;.;.;.;.;T;.
Polyphen
0.17
B;.;.;.;.;.;.
Vest4
0.13
MVP
0.43
MPC
1.4
ClinPred
0.17
T
GERP RS
5.5
Varity_R
0.048
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757800031; hg19: chr2-86459760; API