rs78663177

Positions:

• chr10-110578619-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005445.4(SMC3):​c.351-9T>C variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0456 in 1,598,230 control chromosomes in the GnomAD database, including 1,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (353 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1621 hom.)
• Consequence: SMC3 NM_005445.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.7622
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.07

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 10-110578619-T-C is Benign according to our data. Variant chr10-110578619-T-C is described in ClinVar as [Benign]. Clinvar id is 159986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC3	NM_005445.4	c.351-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361804.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC3	ENST00000361804.5	c.351-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005445.4	P1

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 9014 AN: 152172 Hom.: 352 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0341

Gnomad FIN AF: 0.0504

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0645

GnomAD3 exomes AF: 0.0417 AC: 9831 AN: 235588 Hom.: 269 AF XY: 0.0416 AC XY: 5272 AN XY: 126762

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0271

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.000337

Gnomad SAS exome AF: 0.0339

Gnomad FIN exome AF: 0.0482

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0441 AC: 63790 AN: 1445940 Hom.: 1621 Cov.: 29 AF XY: 0.0438 AC XY: 31480 AN XY: 718574

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0295

Gnomad4 ASJ exome AF: 0.0404

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0353

Gnomad4 FIN exome AF: 0.0484

Gnomad4 NFE exome AF: 0.0445

Gnomad4 OTH exome AF: 0.0477

GnomAD4 genome AF: 0.0593 AC: 9027 AN: 152290 Hom.: 353 Cov.: 32 AF XY: 0.0583 AC XY: 4343 AN XY: 74462

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0406

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0344

Gnomad4 FIN AF: 0.0504

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0515 Hom.: 127

Bravo AF: 0.0603

Asia WGS AF: 0.0220 AC: 77 AN: 3478

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Cornelia de Lange syndrome 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Benign	0.42
SpliceAI score (max)		0.010		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: rs78663177; hg19: chr10-112338377; COSMIC: COSV62419192;