chr15-29268825-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138704.4(NSMCE3):​c.881G>A​(p.Arg294Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 6.8e-7 ( 0 hom. )

Consequence

NSMCE3
NM_138704.4 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20
Variant links:
Genes affected
NSMCE3 (HGNC:7677): (NSE3 homolog, SMC5-SMC6 complex component) The protein encoded by this gene is part of the SMC5-6 chromatin reorganizing complex and is a member of the MAGE superfamily. This is an intronless gene. [provided by RefSeq, May 2011]
ENTREP2 (HGNC:29075): (endosomal transmembrane epsin interactor 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.121034175).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NSMCE3NM_138704.4 linkuse as main transcriptc.881G>A p.Arg294Lys missense_variant 1/1 ENST00000332303.6
ENTREP2NM_015307.2 linkuse as main transcriptc.277-16347G>A intron_variant ENST00000261275.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NSMCE3ENST00000332303.6 linkuse as main transcriptc.881G>A p.Arg294Lys missense_variant 1/1 NM_138704.4 P1
ENTREP2ENST00000261275.5 linkuse as main transcriptc.277-16347G>A intron_variant 5 NM_015307.2 P1O60320-1
ENTREP2ENST00000560082.1 linkuse as main transcriptc.-12-16347G>A intron_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461456
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726968
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 13, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NSMCE3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 294 of the NSMCE3 protein (p.Arg294Lys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
21
DANN
Benign
0.92
DEOGEN2
Benign
0.0079
T
Eigen
Benign
-0.75
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.35
T
M_CAP
Benign
0.0015
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.93
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-0.45
N
REVEL
Benign
0.038
Sift
Benign
0.040
D
Sift4G
Benign
0.094
T
Polyphen
0.10
B
Vest4
0.29
MutPred
0.26
Gain of ubiquitination at R294 (P = 0.0069);
MVP
0.13
MPC
0.45
ClinPred
0.073
T
GERP RS
3.0
Varity_R
0.13
gMVP
0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-29561029; API