rs886037827

Variant names:

• chr15-29269080-G-A
• rs886037827
• NM_138704.4:c.626C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.09

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]

ACMG classification

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 rank	MANE	Protein	UniProt
NSMCE3	NM_138704.4	c.626C>T	p.Pro209Leu	missense_variant	Exon 1 of 1	ENST00000332303.6	NP_619649.1
ENTREP2	NM_015307.2	c.277-16602C>T		intron_variant	Intron 2 of 10	ENST00000261275.5	NP_056122.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSMCE3	ENST00000332303.6	c.626C>T	p.Pro209Leu	missense_variant	Exon 1 of 1	6	NM_138704.4	ENSP00000330694.4
ENTREP2	ENST00000261275.5	c.277-16602C>T		intron_variant	Intron 2 of 10	5	NM_015307.2	ENSP00000261275.4
ENTREP2	ENST00000560082.1	c.-12-16602C>T		intron_variant	Intron 2 of 3	4		ENSP00000452860.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

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.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

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

Submissions by phenotype

Lung damage, immunodeficiency and chromosome breakage syndrome Pathogenic:1

Mar 17, 2016

Sharon E. Plon Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro;in vivo;research

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

Dec 19, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0057	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.15
Sift	Benign	0.034	D
Sift4G	Uncertain	0.048	D
Polyphen		0.76	P
Vest4		0.42
MutPred		0.63		Gain of MoRF binding (P = 0.0346);
MVP		0.67
MPC		1.1
ClinPred		0.99	D
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

Other links and lift over

dbSNP: rs886037827; hg19: chr15-29561284;