rs773917653

Variant names:

• chr8-125366837-A-AAGGG
• rs773917653
• NM_173685.4:c.697_700dupAGGG

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_173685.4(NSMCE2):​c.697_700dupAGGG​(p.Ala234GlufsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000684 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NSMCE2 NM_173685.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0578 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-125366837-A-AAGGG is Pathogenic according to our data. Variant chr8-125366837-A-AAGGG is described in ClinVar as [Pathogenic]. Clinvar id is 372286.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSMCE2	NM_173685.4	c.697_700dupAGGG	p.Ala234GlufsTer4	frameshift_variant	Exon 8 of 8	ENST00000287437.8	NP_775956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSMCE2	ENST00000287437.8	c.697_700dupAGGG	p.Ala234GlufsTer4	frameshift_variant	Exon 8 of 8	1	NM_173685.4	ENSP00000287437.3
NSMCE2	ENST00000522563.5	c.697_700dupAGGG	p.Ala234GlufsTer4	frameshift_variant	Exon 7 of 7	5		ENSP00000430668.1
NSMCE2	ENST00000517315.1	c.517_520dupAGGG	p.Ala174GlufsTer4	frameshift_variant	Exon 7 of 7	3		ENSP00000428846.1
NSMCE2	ENST00000521460.1	n.367_370dupAGGG		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461320 Hom.: 0 Cov.: 29 AF XY: 0.00000825 AC XY: 6 AN XY: 727024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Seckel syndrome 10 Pathogenic:1

Dec 15, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs773917653; hg19: chr8-126379079;