rs199905054

Positions:

chr15-29268916-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_138704.4(NSMCE3):c.790C>T(p.Leu264Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000985 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

NSMCE3
NM_138704.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.39

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-29268916-G-A is Pathogenic according to our data. Variant chr15-29268916-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 267795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-29268916-G-A is described in UniProt as null. Variant chr15-29268916-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.790C>T	p.Leu264Phe	missense_variant	1/1	ENST00000332303.6
ENTREP2	NM_015307.2 linkuse as main transcript	c.277-16438C>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.790C>T	p.Leu264Phe	missense_variant	1/1		NM_138704.4	P1
ENTREP2	ENST00000261275.5 linkuse as main transcript	c.277-16438C>T		intron_variant		5	NM_015307.2	P1	O60320-1
ENTREP2	ENST00000560082.1 linkuse as main transcript	c.-12-16438C>T		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152108

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000755

AC:

AN:

251494

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135922

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:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727246

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:

0.000133

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74422

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 264 of the NSMCE3 protein (p.Leu264Phe). This variant is present in population databases (rs199905054, gnomAD 0.02%). This missense change has been observed in individuals with NSMCE3 deficiency (PMID: 27427983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 267795). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NSMCE3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NSMCE3 function (PMID: 27427983). For these reasons, this variant has been classified as Pathogenic. -

Lung disease, immunodeficiency, and chromosome breakage syndrome;

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2024	Variant summary: NSMCE3 c.790C>T (p.Leu264Phe) results in a non-conservative amino acid change located in the MAGE homology domain (IPR002190) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. c.790C>T has been reported in the literature in multiple individuals affected with Lung Disease, Immunodeficiency, And Chromosome Breakage Syndrome (van der Crabben_2016, Willemse_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33741030, 27427983). ClinVar contains an entry for this variant (Variation ID: 267795). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 19, 2016	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0045

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.99

N;N

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.60

MVP

0.69

MPC

1.3

ClinPred

0.99

GERP RS

3.0

Varity_R

0.86

gMVP

0.61

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.

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