chr8-125316141-G-A

Variant names:

• chr8-125316141-G-A
• rs7004739
• NM_173685.4:c.419-41078G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173685.4(NSMCE2):​c.419-41078G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,036 control chromosomes in the GnomAD database, including 17,609 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (17609 hom., cov: 32)
• Consequence: NSMCE2 NM_173685.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.297
• Publications: 5 publications found

Genes affected

NSMCE2 (HGNC:26513): (NSE2 (MMS21) homolog, SMC5-SMC6 complex SUMO ligase) This gene encodes a member of a family of E3 small ubiquitin-related modifier (SUMO) ligases that mediates the attachment of a SUMO protein to proteins involved in nuclear transport, transcription, chromosome segregation and DNA repair. The encoded protein is part of the structural maintenance of chromosomes (SMC) 5/6 complex which plays a key role genome maintenance, facilitating chromosome segregation and suppressing mitotic recombination. A knockout of the orthologous mouse gene is lethal prior to embryonic day 10.5. Naturally occurring mutations in this gene, that abolish the SUMO ligase activity, are associated with primordial dwarfism and extreme insulin resistance. [provided by RefSeq, Mar 2017]

NSMCE2 Gene-Disease associations (from GenCC):

• Seckel syndrome 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173685.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMCE2	NM_173685.4	MANE Select	c.419-41078G>A		intron	N/A	NP_775956.1
	NSMCE2	NM_001349485.2		c.419-41078G>A		intron	N/A	NP_001336414.1
	NSMCE2	NM_001349486.2		c.419-41078G>A		intron	N/A	NP_001336415.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMCE2	ENST00000287437.8	TSL:1 MANE Select	c.419-41078G>A		intron	N/A	ENSP00000287437.3
	NSMCE2	ENST00000522563.6	TSL:5	c.419-41078G>A		intron	N/A	ENSP00000430668.1
	NSMCE2	ENST00000517532.5	TSL:5	c.419-41078G>A		intron	N/A	ENSP00000429612.1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68029 AN: 151918 Hom.: 17609 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.494

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 68030 AN: 152036 Hom.: 17609 Cov.: 32 AF XY: 0.450 AC XY: 33415 AN XY: 74306

African (AFR) AF: 0.174 AC: 7234 AN: 41498

American (AMR) AF: 0.555 AC: 8463 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2195 AN: 3470

East Asian (EAS) AF: 0.550 AC: 2844 AN: 5174

South Asian (SAS) AF: 0.424 AC: 2046 AN: 4826

European-Finnish (FIN) AF: 0.542 AC: 5713 AN: 10544

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.553 AC: 37595 AN: 67948

Other (OTH) AF: 0.488 AC: 1031 AN: 2112

Alfa AF: 0.507 Hom.: 6649

Bravo AF: 0.443

Asia WGS AF: 0.427 AC: 1487 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.35
DANN	Benign	0.65
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs7004739; hg19: chr8-126328383;