2-86337501-A-T

Variant names:

• chr2-86337501-A-T
• rs863224189
• NM_001371279.1:c.10T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001164731.2(REEP1):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: REEP1 NM_001164731.2 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 12 codons. Genomic position: 86264032. Lost 0.065 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164731.2. 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.10T>A	p.Trp4Arg	missense	Exon 1 of 9	NP_001358208.1	A0A1C7CYY3
	REEP1	NM_001164731.2		c.2T>A	p.Met1?	start_lost	Exon 1 of 6	NP_001158203.1	Q9H902-2
	REEP1	NM_001410855.1		c.10T>A	p.Trp4Arg	missense	Exon 1 of 8	NP_001397784.1	A0A2R8Y6K6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	ENST00000538924.7	TSL:5 MANE Select	c.10T>A	p.Trp4Arg	missense	Exon 1 of 9	ENSP00000438346.3	A0A1C7CYY3
	REEP1	ENST00000165698.9	TSL:1	c.10T>A	p.Trp4Arg	missense	Exon 1 of 7	ENSP00000165698.5	Q9H902-1
	REEP1	ENST00000686220.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 7	ENSP00000509904.1	A0A8I5KTX0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Benign	0.94
Eigen	Benign	-0.0076
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.37	D
PhyloP100		2.9
PROVEAN	Benign	5.3	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Vest4		0.47
MutPred		0.53		Loss of stability (P = 0.0048)
MVP		0.17
ClinPred		0.83	D
GERP RS		2.8
PromoterAI		-0.034	Neutral
Varity_R		0.51
Mutation Taster		=87/113	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs863224189; hg19: chr2-86564624;