Genetic Variant NM_001001330.3:c.668C>G (chr10-63619757-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001001330.3(REEP3):c.668C>G(p.Ser223Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,457,618 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S223L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

REEP3
NM_001001330.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

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 link	c.668C>G	p.Ser223Trp	missense_variant	Exon 7 of 8	ENST00000373758.5	NP_001001330.1	Q6NUK4-1X5DR89
LOC105378329	XR_001747467.3 link	n.295+5062G>C		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
REEP3	ENST00000373758.5 link	c.668C>G	p.Ser223Trp	missense_variant	Exon 7 of 8	1	NM_001001330.3	ENSP00000362863.4	Q6NUK4-1
REEP3	ENST00000634963.1 link	n.*252C>G		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000489394.1	A0A0U1RR85
REEP3	ENST00000634963.1 link	n.*252C>G		3_prime_UTR_variant	Exon 5 of 6	5		ENSP00000489394.1	A0A0U1RR85

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1457618

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

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:

0.00

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:

0.00000360

AC:

AN:

1110046

Other (OTH)

AF:

0.00

AC:

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.61

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.6

PhyloP100

5.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.47

MutPred

0.34

Loss of phosphorylation at S223 (P = 0.0049);

MVP

0.97

MPC

1.3

ClinPred

0.99

GERP RS

5.7

Varity_R

0.49

gMVP

0.61

Mutation Taster

=51/49

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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NM_001001330.3:c.668C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over