Genetic Variant REEP3:p.Ser223Leu (chr10-63619757-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001001330.3(REEP3):c.668C>T(p.Ser223Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000354 in 1,609,656 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: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

REEP3
NM_001001330.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.11

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14686108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP3	NM_001001330.3 link	c.668C>T	p.Ser223Leu	missense_variant	Exon 7 of 8	ENST00000373758.5	NP_001001330.1	Q6NUK4-1X5DR89
LOC105378329	XR_001747467.3 link	n.295+5062G>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
REEP3	ENST00000373758.5 link	c.668C>T	p.Ser223Leu	missense_variant	Exon 7 of 8	1	NM_001001330.3	ENSP00000362863.4	Q6NUK4-1
REEP3	ENST00000634963.1 link	n.*252C>T		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000489394.1	A0A0U1RR85
REEP3	ENST00000634963.1 link	n.*252C>T		3_prime_UTR_variant	Exon 5 of 6	5		ENSP00000489394.1	A0A0U1RR85

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

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:

0.0000619

AC:

AN:

242410

AF XY:

0.0000305

show subpopulations

Gnomad AFR exome

AF:

0.000809

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000910

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1457616

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

724496

show subpopulations

African (AFR)

AF:

0.000479

AC:

AN:

33436

American (AMR)

AF:

0.0000226

AC:

AN:

44188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26016

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.0000353

AC:

AN:

85086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1110046

Other (OTH)

AF:

0.0000498

AC:

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000184

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.000555

AC:

AN:

41406

American (AMR)

AF:

0.000131

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.000795

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.668C>T (p.S223L) alteration is located in exon 7 (coding exon 7) of the REEP3 gene. This alteration results from a C to T substitution at nucleotide position 668, causing the serine (S) at amino acid position 223 to be replaced by a leucine (L). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.15

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.6

PhyloP100

5.1

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

Sift4G

Benign

0.096

Polyphen

0.98

Vest4

0.27

MVP

0.96

MPC

0.53

ClinPred

0.15

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.55

Mutation Taster

=60/40

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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10-63619757-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over