dbSNP rs387906263: REEP1:p.Pro171HisfsTer46 (chr2-86232707-TG-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001371279.1(REEP1):c.512delC(p.Pro171HisfsTer46) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,458,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

REEP1
NM_001371279.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.59

Publications

3 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-86232707-TG-T is Pathogenic according to our data. Variant chr2-86232707-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371279.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
REEP1	NM_001371279.1	MANE Select	c.512delC	p.Pro171HisfsTer46	frameshift	Exon 6 of 9	NP_001358208.1	A0A1C7CYY3
REEP1	NM_001410855.1		c.512delC	p.Pro171HisfsTer34	frameshift	Exon 6 of 8	NP_001397784.1	A0A2R8Y6K6
REEP1	NM_001410856.1		c.512delC	p.Pro171HisfsTer64	frameshift	Exon 6 of 8	NP_001397785.1	A0A8I5QKJ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
REEP1	ENST00000538924.7	TSL:5 MANE Select	c.512delC	p.Pro171HisfsTer46	frameshift	Exon 6 of 9	ENSP00000438346.3	A0A1C7CYY3
REEP1	ENST00000165698.9	TSL:1	c.512delC	p.Pro171HisfsTer52	frameshift	Exon 6 of 7	ENSP00000165698.5	Q9H902-1
REEP1	ENST00000908467.1		c.662delC	p.Pro221HisfsTer34	frameshift	Exon 7 of 9	ENSP00000578526.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458782

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000198

AC:

AN:

50414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 31 (3)

Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.6

Mutation Taster

=1/199

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over