Genetic Variant REEP3:p.Val138Ile (chr10-63599278-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001001330.3(REEP3):c.412G>A(p.Val138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,293,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

REEP3
NM_001001330.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

Publications

0 publications found

Variant links:

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]

REEP3 links:

LOC105378329 (HGNC:):

LOC105378329 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26441807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP3	NM_001001330.3 link	c.412G>A	p.Val138Ile	missense_variant	Exon 5 of 8	ENST00000373758.5	NP_001001330.1	Q6NUK4-1X5DR89
REEP3	XM_011539501.3 link	c.412G>A	p.Val138Ile	missense_variant	Exon 5 of 6		XP_011537803.1	X5DP57
REEP3	XM_017015896.2 link	c.412G>A	p.Val138Ile	missense_variant	Exon 5 of 7		XP_016871385.1	X5DP57
LOC105378329	XR_001747467.3 link	n.412-3182C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP3	ENST00000373758.5 link	c.412G>A	p.Val138Ile	missense_variant	Exon 5 of 8	1	NM_001001330.3	ENSP00000362863.4		Q6NUK4-1
REEP3	ENST00000634963.1 link	n.208G>A		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000489394.1		A0A0U1RR85

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000618

AC:

AN:

1293660

Hom.:

Cov.:

AF XY:

0.00000772

AC XY:

AN XY:

647402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27160

American (AMR)

AF:

0.00

AC:

AN:

26490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23452

East Asian (EAS)

AF:

0.00

AC:

AN:

34998

South Asian (SAS)

AF:

0.00

AC:

AN:

70120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5446

European-Non Finnish (NFE)

AF:

0.00000700

AC:

AN:

999336

Other (OTH)

AF:

0.0000184

AC:

AN:

54244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.412G>A (p.V138I) alteration is located in exon 5 (coding exon 5) of the REEP3 gene. This alteration results from a G to A substitution at nucleotide position 412, causing the valine (V) at amino acid position 138 to be replaced by an isoleucine (I). 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

0.16

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0085

Eigen

Benign

0.052

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

M_CAP

Benign

0.040

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.6

PhyloP100

3.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.71

REVEL

Uncertain

0.36

Sift

Benign

0.71

Sift4G

Benign

0.93

Polyphen

0.89

Vest4

0.29

MutPred

0.33

Gain of loop (P = 0.0111);

MVP

0.83

MPC

0.28

ClinPred

0.75

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.50

Mutation Taster

=92/8

polymorphism

(source)

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

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chr10-63599278-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over