rs757613817

Variant names:

• chr8-125182182-AT-A
• rs757613817
• NM_173685.4:c.346delT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_173685.4(NSMCE2):​c.346delT​(p.Ser116LeufsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,606,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: NSMCE2 NM_173685.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.29
• Publications: 0 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, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-125182182-AT-A is Pathogenic according to our data. Variant chr8-125182182-AT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 372285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMCE2	NM_173685.4	MANE Select	c.346delT	p.Ser116LeufsTer18	frameshift	Exon 5 of 8	NP_775956.1	Q96MF7
	NSMCE2	NM_001349485.2		c.346delT	p.Ser116LeufsTer18	frameshift	Exon 4 of 7	NP_001336414.1	Q96MF7
	NSMCE2	NM_001349486.2		c.346delT	p.Ser116LeufsTer18	frameshift	Exon 5 of 8	NP_001336415.1	Q96MF7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMCE2	ENST00000287437.8	TSL:1 MANE Select	c.346delT	p.Ser116LeufsTer18	frameshift	Exon 5 of 8	ENSP00000287437.3	Q96MF7
	NSMCE2	ENST00000897054.1		c.406delT	p.Ser136LeufsTer18	frameshift	Exon 6 of 9	ENSP00000567113.1
	NSMCE2	ENST00000522563.6	TSL:5	c.346delT	p.Ser116LeufsTer18	frameshift	Exon 4 of 7	ENSP00000430668.1	Q96MF7

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.000279

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000174 AC: 43 AN: 246764 AF XY: 0.000195

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000224 AC: 326 AN: 1454502 Hom.: 0 Cov.: 28 AF XY: 0.000211 AC XY: 153 AN XY: 723684

African (AFR) AF: 0.0000302 AC: 1 AN: 33152

American (AMR) AF: 0.000228 AC: 10 AN: 43878

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 84872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5714

European-Non Finnish (NFE) AF: 0.000267 AC: 296 AN: 1107682

Other (OTH) AF: 0.000266 AC: 16 AN: 60138

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74500

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000178

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Seckel syndrome 10 (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs757613817; hg19: chr8-126194424;