rs786204081

Variant names:

• chr2-86251959-T-A
• rs786204081
• NM_001371279.1:c.415A>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_001371279.1(REEP1):​c.415A>T​(p.Lys139*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: REEP1 NM_001371279.1 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.90
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 13 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
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-86251959-T-A is Pathogenic according to our data. Variant chr2-86251959-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 188118.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	NM_001371279.1	MANE Select	c.415A>T	p.Lys139*	stop_gained splice_region	Exon 5 of 9	NP_001358208.1	A0A1C7CYY3
	REEP1	NM_001410855.1		c.415A>T	p.Lys139*	stop_gained splice_region	Exon 5 of 8	NP_001397784.1	A0A2R8Y6K6
	REEP1	NM_001410856.1		c.415A>T	p.Lys139*	stop_gained splice_region	Exon 5 of 8	NP_001397785.1	A0A8I5QKJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	ENST00000538924.7	TSL:5 MANE Select	c.415A>T	p.Lys139*	stop_gained splice_region	Exon 5 of 9	ENSP00000438346.3	A0A1C7CYY3
	REEP1	ENST00000165698.9	TSL:1	c.415A>T	p.Lys139*	stop_gained splice_region	Exon 5 of 7	ENSP00000165698.5	Q9H902-1
	REEP1	ENST00000489855.2	TSL:3	c.349A>T	p.Lys117*	stop_gained	Exon 4 of 4	ENSP00000475269.1	U3KPV7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary spastic paraplegia 31 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.9
Vest4		0.92
GERP RS		5.8
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786204081; hg19: chr2-86479082;