Genetic Variant REEP3:p.Lys179Glu (chr10-63610304-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001001330.3(REEP3):c.535A>G(p.Lys179Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000425 in 1,411,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

REEP3
NM_001001330.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22047588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP3	NM_001001330.3 link	c.535A>G	p.Lys179Glu	missense_variant	Exon 6 of 8	ENST00000373758.5	NP_001001330.1	Q6NUK4-1X5DR89
LOC105378329	XR_001747467.3 link	n.411+4273T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
REEP3	ENST00000373758.5 link	c.535A>G	p.Lys179Glu	missense_variant	Exon 6 of 8	1	NM_001001330.3	ENSP00000362863.4	Q6NUK4-1
REEP3	ENST00000634963.1 link	n.*119A>G		non_coding_transcript_exon_variant	Exon 4 of 6	5		ENSP00000489394.1	A0A0U1RR85
REEP3	ENST00000634963.1 link	n.*119A>G		3_prime_UTR_variant	Exon 4 of 6	5		ENSP00000489394.1	A0A0U1RR85

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

172682

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000425

AC:

AN:

1411136

Hom.:

Cov.:

AF XY:

0.00000574

AC XY:

AN XY:

697038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32224

American (AMR)

AF:

0.00

AC:

AN:

36720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25322

East Asian (EAS)

AF:

0.0000268

AC:

AN:

37374

South Asian (SAS)

AF:

0.00

AC:

AN:

80354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00000461

AC:

AN:

1084372

Other (OTH)

AF:

0.00

AC:

AN:

58638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000872

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.535A>G (p.K179E) alteration is located in exon 6 (coding exon 6) of the REEP3 gene. This alteration results from a A to G substitution at nucleotide position 535, causing the lysine (K) at amino acid position 179 to be replaced by a glutamic acid (E). 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

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

Eigen

Benign

0.065

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.70

M_CAP

Benign

0.017

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.3

PhyloP100

4.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.33

Sift

Benign

0.20

Sift4G

Benign

0.95

Polyphen

0.65

Vest4

0.39

MutPred

0.21

Loss of ubiquitination at K179 (P = 0.0155);

MVP

0.87

MPC

0.47

ClinPred

0.58

GERP RS

6.0

Varity_R

0.17

gMVP

0.17

Mutation Taster

=84/16

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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chr10-63610304-A-G

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