10-63598124-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001001330.3(REEP3):c.283C>G(p.Leu95Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: REEP3 NM_001001330.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29148635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REEP3	NM_001001330.3	c.283C>G	p.Leu95Val	missense_variant	4/8	ENST00000373758.5
LOC105378329	XR_001747467.3	n.412-2028G>C		intron_variant, non_coding_transcript_variant
REEP3	XM_011539501.3	c.283C>G	p.Leu95Val	missense_variant	4/6
REEP3	XM_017015896.2	c.283C>G	p.Leu95Val	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REEP3	ENST00000373758.5	c.283C>G	p.Leu95Val	missense_variant	4/8	1	NM_001001330.3	P1
REEP3	ENST00000634963.1	c.79C>G	p.Leu27Val	missense_variant, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000204 AC: 5 AN: 245184 Hom.: 0 AF XY: 0.0000300 AC XY: 4 AN XY: 133132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000284

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435222 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 715606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.283C>G (p.L95V) alteration is located in exon 4 (coding exon 4) of the REEP3 gene. This alteration results from a C to G substitution at nucleotide position 283, causing the leucine (L) at amino acid position 95 to be replaced by a valine (V). 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	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.060	D
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.30
Sift	Benign	0.40	T
Sift4G	Benign	0.50	T
Polyphen		0.72	P
Vest4		0.34
MutPred		0.43		Gain of methylation at K99 (P = 0.0601);
MVP		0.73
MPC		0.36
ClinPred		0.070	T
GERP RS		5.0
Varity_R		0.16
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs760168466; hg19: chr10-65357884;