rs587784428

chr10-110581915-C-CTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005445.4(SMC3):c.548-5_548-4dup 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 0.0456 in 1,610,522 control chromosomes in the GnomAD database, including 1,987 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (349 hom., cov: 31)
  • Exomes 𝑓: 0.044 (1638 hom.)
• Consequence: SMC3 NM_005445.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.55

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 -16 ACMG points.

• BP6: Variant 10-110581915-C-CTT is Benign according to our data. Variant chr10-110581915-C-CTT is described in ClinVar as [Likely_benign]. Clinvar id is 159989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC3	NM_005445.4	c.548-5_548-4dup		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.548-5_548-4dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005445.4	P1

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 8995 AN: 152064 Hom.: 348 Cov.: 31

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0651

GnomAD3 exomes AF: 0.0422 AC: 10565 AN: 250438 Hom.: 294 AF XY: 0.0424 AC XY: 5748 AN XY: 135682

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0273

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0361

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0449

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0442 AC: 64512 AN: 1458340 Hom.: 1638 Cov.: 31 AF XY: 0.0440 AC XY: 31927 AN XY: 725718

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0295

Gnomad4 ASJ exome AF: 0.0403

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.0483

Gnomad4 NFE exome AF: 0.0445

Gnomad4 OTH exome AF: 0.0479

GnomAD4 genome AF: 0.0592 AC: 9007 AN: 152182 Hom.: 349 Cov.: 31 AF XY: 0.0584 AC XY: 4343 AN XY: 74418

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0406

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.0503

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0644

Alfa AF: 0.0497 Hom.: 48

Bravo AF: 0.0601

Asia WGS AF: 0.0230 AC: 80 AN: 3476

EpiCase AF: 0.0454

EpiControl AF: 0.0445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2017	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cornelia de Lange syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

De Lange syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs199906378; hg19: chr10-112341673;