NM_138704.4:c.826A>G

Variant names:

• chr15-29268880-T-C
• rs987175109
• NM_138704.4:c.826A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138704.4(NSMCE3):​c.826A>G​(p.Lys276Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NSMCE3 NM_138704.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.556
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17477545).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138704.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMCE3	NM_138704.4	MANE Select	c.826A>G	p.Lys276Glu	missense	Exon 1 of 1	NP_619649.1	Q96MG7
	ENTREP2	NM_015307.2	MANE Select	c.277-16402A>G		intron	N/A	NP_056122.1	O60320-1
	ENTREP2	NM_001387214.1		c.277-16402A>G		intron	N/A	NP_001374143.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMCE3	ENST00000332303.6	TSL:6 MANE Select	c.826A>G	p.Lys276Glu	missense	Exon 1 of 1	ENSP00000330694.4	Q96MG7
	ENTREP2	ENST00000261275.5	TSL:5 MANE Select	c.277-16402A>G		intron	N/A	ENSP00000261275.4	O60320-1
	ENTREP2	ENST00000918355.1		c.277-16402A>G		intron	N/A	ENSP00000588414.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.87	T
PhyloP100		0.56
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.069
Sift	Uncertain	0.016	D
Sift4G	Benign	0.12	T
Polyphen		0.23	B
Vest4		0.36
MVP		0.26
MPC		0.62
ClinPred		0.75	D
GERP RS		3.9
Varity_R		0.65
gMVP		0.42
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs987175109; hg19: chr15-29561084;