rs11195199

Positions:

• chr10-110583833-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005445.4(SMC3):​c.970-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,608,740 control chromosomes in the GnomAD database, including 12,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1221 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11504 hom.)
• Consequence: SMC3 NM_005445.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001165
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.25

Genes affected

SMC3 (HGNC:2468): (structural maintenance of chromosomes 3) This gene belongs to the SMC3 subfamily of SMC proteins. The encoded protein occurs in certain cell types as either an intracellular, nuclear protein or a secreted protein. The nuclear form, known as structural maintenance of chromosomes 3, is a component of the multimeric cohesin complex that holds together sister chromatids during mitosis, enabling proper chromosome segregation. Post-translational modification of the encoded protein by the addition of chondroitin sulfate chains gives rise to the secreted proteoglycan bamacan, an abundant basement membrane protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-110583833-G-A is Benign according to our data. Variant chr10-110583833-G-A is described in ClinVar as [Benign]. Clinvar id is 159992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110583833-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC3	NM_005445.4	c.970-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000361804.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC3	ENST00000361804.5	c.970-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005445.4	P1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17725 AN: 151818 Hom.: 1217 Cov.: 32

Gnomad AFR AF: 0.0827

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.151 AC: 37473 AN: 248774 Hom.: 3330 AF XY: 0.148 AC XY: 19939 AN XY: 134944

Gnomad AFR exome AF: 0.0836

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.247

Gnomad SAS exome AF: 0.179

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.115 AC: 167743 AN: 1456804 Hom.: 11504 Cov.: 32 AF XY: 0.117 AC XY: 84795 AN XY: 724704

Gnomad4 AFR exome AF: 0.0808

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.0980

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.117 AC: 17751 AN: 151936 Hom.: 1221 Cov.: 32 AF XY: 0.122 AC XY: 9055 AN XY: 74276

Gnomad4 AFR AF: 0.0828

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.131

Alfa AF: 0.107 Hom.: 992

Bravo AF: 0.119

Asia WGS AF: 0.213 AC: 740 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.109

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Cornelia de Lange syndrome 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs11195199; hg19: chr10-112343591; COSMIC: COSV62418757; COSMIC: COSV62418757;