rs886037827

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_138704.4(NSMCE3):c.626C>T(p.Pro209Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

NSMCE3
NM_138704.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.09

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]

NSMCE3 links:

ENTREP2 (HGNC:29075): (endosomal transmembrane epsin interactor 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENTREP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-29269080-G-A is Pathogenic according to our data. Variant chr15-29269080-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 267796.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-29269080-G-A is described in UniProt as null. Variant chr15-29269080-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSMCE3	NM_138704.4 linkuse as main transcript	c.626C>T	p.Pro209Leu	missense_variant	1/1	ENST00000332303.6
ENTREP2	NM_015307.2 linkuse as main transcript	c.277-16602C>T		intron_variant		ENST00000261275.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSMCE3	ENST00000332303.6 linkuse as main transcript	c.626C>T	p.Pro209Leu	missense_variant	1/1		NM_138704.4	P1
ENTREP2	ENST00000261275.5 linkuse as main transcript	c.277-16602C>T		intron_variant		5	NM_015307.2	P1	O60320-1
ENTREP2	ENST00000560082.1 linkuse as main transcript	c.-12-16602C>T		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lung damage, immunodeficiency and chromosome breakage syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;in vivo;research

Sharon E. Plon Laboratory, Baylor College of Medicine

Mar 17, 2016

Four siblings from two unrelated kindreds died during infancy with markedly similar medical problems including severe pulmonary disease following viral pneumonia with evidence of combined T- and B-cell immunodeficiency. Chromosomal testing showed signs of increased aneuploidy/breakage. Cells from the subjects had increased sensitivity to DNA damage. One sib pair harbored rare (p.Leu264Phe) and novel (p.Pro209Leu) compound heterozygous missense variants in NSMCE3, while the other sib pair was homozygous for the p.Leu264Phe variant in NSMCE3. -

Lung disease, immunodeficiency, and chromosome breakage syndrome;

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.058

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.73

M_CAP

Benign

0.0057

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.15

Sift

Benign

0.034

Sift4G

Uncertain

0.048

Polyphen

0.76

Vest4

0.42

MutPred

0.63

Gain of MoRF binding (P = 0.0346);

MVP

0.67

MPC

1.1

ClinPred

0.99

GERP RS

4.1

Varity_R

0.27

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over