NM_001371279.1:c.166G>A

Variant names:

• chr2-86263981-C-T
• rs1060503493
• NM_001371279.1:c.166G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001371279.1(REEP1):​c.166G>A​(p.Asp56Asn) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D56H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: REEP1 NM_001371279.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.86
• Publications: 4 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-86263981-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 989225.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

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.166G>A	p.Asp56Asn	missense	Exon 3 of 9	NP_001358208.1	A0A1C7CYY3
	REEP1	NM_001410855.1		c.166G>A	p.Asp56Asn	missense	Exon 3 of 8	NP_001397784.1	A0A2R8Y6K6
	REEP1	NM_001410856.1		c.166G>A	p.Asp56Asn	missense	Exon 3 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.166G>A	p.Asp56Asn	missense	Exon 3 of 9	ENSP00000438346.3	A0A1C7CYY3
	REEP1	ENST00000165698.9	TSL:1	c.166G>A	p.Asp56Asn	missense	Exon 3 of 7	ENSP00000165698.5	Q9H902-1
	REEP1	ENST00000908467.1		c.166G>A	p.Asp56Asn	missense	Exon 3 of 9	ENSP00000578526.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 31 (1)
-	1	-	Neuronopathy, distal hereditary motor, type 5B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.59		Loss of sheet (P = 0.0457)
MVP		0.91
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.93
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs1060503493; hg19: chr2-86491104;