rs863224189

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-86337501-A-C
• chr2-86337501-A-G
• chr2-86337501-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_001164731.2(REEP1):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 1,297,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: REEP1 NM_001164731.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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 2 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.

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>G	p.Trp4Gly	missense	Exon 1 of 9	NP_001358208.1	A0A1C7CYY3
	REEP1	NM_001164731.2		c.2T>G	p.Met1?	start_lost	Exon 1 of 6	NP_001158203.1	Q9H902-2
	REEP1	NM_001410855.1		c.10T>G	p.Trp4Gly	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>G	p.Trp4Gly	missense	Exon 1 of 9	ENSP00000438346.3	A0A1C7CYY3
	REEP1	ENST00000165698.9	TSL:1	c.10T>G	p.Trp4Gly	missense	Exon 1 of 7	ENSP00000165698.5	Q9H902-1
	REEP1	ENST00000686220.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000509904.1	A0A8I5KTX0

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150314 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000436 AC: 5 AN: 1147504 Hom.: 0 Cov.: 30 AF XY: 0.00000538 AC XY: 3 AN XY: 557588

African (AFR) AF: 0.00 AC: 0 AN: 23348

American (AMR) AF: 0.00 AC: 0 AN: 15024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16808

East Asian (EAS) AF: 0.00 AC: 0 AN: 24940

South Asian (SAS) AF: 0.00 AC: 0 AN: 38152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3096

European-Non Finnish (NFE) AF: 0.00000527 AC: 5 AN: 947952

Other (OTH) AF: 0.00 AC: 0 AN: 44870

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150314 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73370

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000243 AC: 1 AN: 41174

American (AMR) AF: 0.00 AC: 0 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67384

Other (OTH) AF: 0.00 AC: 0 AN: 2058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 31 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	REEP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	31
DANN	Benign	0.93
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.39	T
PhyloP100		2.9
PROVEAN	Benign	3.4	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Vest4		0.39
MutPred		0.50		Loss of stability (P = 0.0576)
MVP		0.12
ClinPred		0.24	T
GERP RS		2.8
PromoterAI		-0.048	Neutral
Varity_R		0.57
Mutation Taster		=87/113	disease causing

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

Other links and lift over

dbSNP: rs863224189; hg19: chr2-86564624;