chr15-29268868-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138704.4(NSMCE3):​c.838G>T​(p.Ala280Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A280V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NSMCE3
NM_138704.4 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0240
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.028853595).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NSMCE3NM_138704.4 linkuse as main transcriptc.838G>T p.Ala280Ser missense_variant 1/1 ENST00000332303.6
ENTREP2NM_015307.2 linkuse as main transcriptc.277-16390G>T intron_variant ENST00000261275.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NSMCE3ENST00000332303.6 linkuse as main transcriptc.838G>T p.Ala280Ser missense_variant 1/1 NM_138704.4 P1
ENTREP2ENST00000261275.5 linkuse as main transcriptc.277-16390G>T intron_variant 5 NM_015307.2 P1O60320-1
ENTREP2ENST00000560082.1 linkuse as main transcriptc.-12-16390G>T intron_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
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), LabcorpJan 07, 2022In 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 alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 280 of the NSMCE3 protein (p.Ala280Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
13
DANN
Benign
0.93
DEOGEN2
Benign
0.0012
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.048
N
LIST_S2
Benign
0.23
T
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.029
T
MetaSVM
Benign
-0.91
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.53
N
REVEL
Benign
0.019
Sift
Benign
0.56
T
Sift4G
Benign
0.91
T
Polyphen
0.0070
B
Vest4
0.13
MutPred
0.30
Gain of ubiquitination at K276 (P = 0.0662);
MVP
0.13
MPC
0.41
ClinPred
0.090
T
GERP RS
1.9
Varity_R
0.057
gMVP
0.26

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: chr15-29561072; API