Genetic Variant REEP1:p.Gly142Cys (chr2-86232796-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001371279.1(REEP1):c.424G>T(p.Gly142Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G142R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

REEP1
NM_001371279.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.24

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP1	NM_001371279.1 link	c.424G>T	p.Gly142Cys	missense_variant	Exon 6 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.424G>T	p.Gly142Cys	missense_variant	Exon 6 of 9	5	NM_001371279.1	ENSP00000438346.3		A0A1C7CYY3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111872

Other (OTH)

AF:

0.00

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.;.;.;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.4

M;.;.;.;.;.;.

PhyloP100

5.2

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-8.0

D;.;.;.;.;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;.;.;.;.;D;D

Sift4G

Pathogenic

0.0010

D;.;.;.;.;D;.

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.79

MutPred

0.39

Loss of disorder (P = 0.049);.;.;Loss of disorder (P = 0.049);.;.;.;

MVP

0.88

MPC

2.0

ClinPred

1.0

GERP RS

4.8

Varity_R

0.82

gMVP

0.84

Mutation Taster

=58/42

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over