15-29268817-G-A

Variant summary

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

The NM_138704.4(NSMCE3):​c.889C>T​(p.Pro297Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,612,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

NSMCE3
NM_138704.4 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.266
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 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=0.04016778).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NSMCE3NM_138704.4 linkuse as main transcriptc.889C>T p.Pro297Ser missense_variant 1/1 ENST00000332303.6
ENTREP2NM_015307.2 linkuse as main transcriptc.277-16339C>T intron_variant ENST00000261275.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NSMCE3ENST00000332303.6 linkuse as main transcriptc.889C>T p.Pro297Ser missense_variant 1/1 NM_138704.4 P1
ENTREP2ENST00000261275.5 linkuse as main transcriptc.277-16339C>T intron_variant 5 NM_015307.2 P1O60320-1
ENTREP2ENST00000560082.1 linkuse as main transcriptc.-12-16339C>T intron_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152110
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
250618
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135360
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000530
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000534
AC:
78
AN:
1459960
Hom.:
0
Cov.:
31
AF XY:
0.0000510
AC XY:
37
AN XY:
725846
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:
0.0000693
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152110
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000823
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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), LabcorpMar 05, 2022This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 297 of the NSMCE3 protein (p.Pro297Ser). This variant is present in population databases (rs776476342, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with NSMCE3-related conditions. 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. In 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
3.4
DANN
Benign
0.70
DEOGEN2
Benign
0.0017
T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.051
N
LIST_S2
Benign
0.52
T
M_CAP
Benign
0.0020
T
MetaRNN
Benign
0.040
T
MetaSVM
Benign
-0.92
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
0.76
N
REVEL
Benign
0.030
Sift
Benign
0.14
T
Sift4G
Benign
0.24
T
Polyphen
0.021
B
Vest4
0.16
MVP
0.055
MPC
0.44
ClinPred
0.033
T
GERP RS
-7.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.023
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776476342; hg19: chr15-29561021; COSMIC: COSV99724151; API