rs562968137

Variant names:

• chr10-63599233-C-T
• rs562968137
• NM_001001330.3:c.367C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001001330.3(REEP3):​c.367C>T​(p.Arg123Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000138 in 1,588,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: REEP3 NM_001001330.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26
• Publications: 0 publications found

Genes affected

REEP3 (HGNC:23711): (receptor accessory protein 3) Predicted to enable microtubule binding activity. Involved in mitotic nuclear membrane reassembly. Predicted to be integral component of membrane. Predicted to be active in cytoplasmic microtubule; endoplasmic reticulum membrane; and endoplasmic reticulum tubular network. [provided by Alliance of Genome Resources, Apr 2022]

LOC105378329 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP3	NM_001001330.3	c.367C>T	p.Arg123Trp	missense_variant	Exon 5 of 8	ENST00000373758.5	NP_001001330.1
REEP3	XM_011539501.3	c.367C>T	p.Arg123Trp	missense_variant	Exon 5 of 6		XP_011537803.1
REEP3	XM_017015896.2	c.367C>T	p.Arg123Trp	missense_variant	Exon 5 of 7		XP_016871385.1
LOC105378329	XR_001747467.3	n.412-3137G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP3	ENST00000373758.5	c.367C>T	p.Arg123Trp	missense_variant	Exon 5 of 8	1	NM_001001330.3	ENSP00000362863.4
REEP3	ENST00000634963.1	n.163C>T		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000489394.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000176 AC: 4 AN: 227224 AF XY: 0.0000161

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 20 AN: 1436430 Hom.: 0 Cov.: 27 AF XY: 0.0000112 AC XY: 8 AN XY: 714418

African (AFR) AF: 0.00 AC: 0 AN: 32004

American (AMR) AF: 0.00 AC: 0 AN: 38666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25660

East Asian (EAS) AF: 0.00 AC: 0 AN: 38224

South Asian (SAS) AF: 0.0000369 AC: 3 AN: 81398

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000145 AC: 16 AN: 1102146

Other (OTH) AF: 0.00 AC: 0 AN: 59432

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000828 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.367C>T (p.R123W) alteration is located in exon 5 (coding exon 5) of the REEP3 gene. This alteration results from a C to T substitution at nucleotide position 367, causing the arginine (R) at amino acid position 123 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.57		Loss of methylation at R123 (P = 0.0087);
MVP		0.98
MPC		1.1
ClinPred		0.80	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.80
Mutation Taster		=79/21	polymorphism

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: rs562968137; hg19: chr10-65358993;