16-27235209-G-C

Variant names:

• chr16-27235209-G-C
• rs766791420
• NM_145080.4:c.227C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145080.4(NSMCE1):​c.227C>G​(p.Thr76Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T76M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NSMCE1 NM_145080.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.87
• Publications: 0 publications found

Genes affected

NSMCE1 (HGNC:29897): (NSE1 homolog, SMC5-SMC6 complex component) Enables protein dimerization activity and ubiquitin protein ligase activity. Involved in positive regulation of response to DNA damage stimulus. Located in nucleoplasm. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31218028).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145080.4. 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
	NSMCE1	NM_145080.4	MANE Select	c.227C>G	p.Thr76Arg	missense	Exon 3 of 8	NP_659547.2	Q8WV22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMCE1	ENST00000361439.9	TSL:1 MANE Select	c.227C>G	p.Thr76Arg	missense	Exon 3 of 8	ENSP00000355077.4	Q8WV22
	NSMCE1	ENST00000869101.1		c.359C>G	p.Thr120Arg	missense	Exon 4 of 9	ENSP00000539160.1
	NSMCE1	ENST00000869102.1		c.227C>G	p.Thr76Arg	missense	Exon 3 of 9	ENSP00000539161.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		4.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.23	T
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.37		Gain of solvent accessibility (P = 0.0086)
MVP		0.33
MPC		1.3
ClinPred		0.95	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.59

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: rs766791420; hg19: chr16-27246530;