rs75323904

Positions:

• chr10-110589664-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005445.4(SMC3):​c.1365T>C​(p.Tyr455=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,609,758 control chromosomes in the GnomAD database, including 2,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (354 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1646 hom.)
• Consequence: SMC3 NM_005445.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0440

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-110589664-T-C is Benign according to our data. Variant chr10-110589664-T-C is described in ClinVar as [Benign]. Clinvar id is 159967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110589664-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.044 with no splicing effect.
• 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	Protein	UniProt
SMC3	NM_005445.4	c.1365T>C	p.Tyr455=	synonymous_variant	14/29	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.1365T>C	p.Tyr455=	synonymous_variant	14/29	1	NM_005445.4	ENSP00000354720	P1

Frequencies

GnomAD3 genomes AF: 0.0593 AC: 9015 AN: 152118 Hom.: 353 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.0506

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0651

GnomAD3 exomes AF: 0.0422 AC: 10552 AN: 249876 Hom.: 293 AF XY: 0.0424 AC XY: 5731 AN XY: 135216

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0274

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0360

Gnomad FIN exome AF: 0.0479

Gnomad NFE exome AF: 0.0450

Gnomad OTH exome AF: 0.0501

GnomAD4 exome AF: 0.0442 AC: 64417 AN: 1457522 Hom.: 1646 Cov.: 29 AF XY: 0.0439 AC XY: 31877 AN XY: 725310

Gnomad4 AFR exome AF: 0.110

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: 0.0444

Gnomad4 OTH exome AF: 0.0479

GnomAD4 genome AF: 0.0593 AC: 9031 AN: 152236 Hom.: 354 Cov.: 33 AF XY: 0.0585 AC XY: 4354 AN XY: 74440

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0404

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.0506

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0644

Alfa AF: 0.0506 Hom.: 138

Bravo AF: 0.0602

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.0454

EpiControl AF: 0.0446

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cornelia de Lange syndrome 3 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2016

This alteration is classified as 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.5
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs75323904; hg19: chr10-112349422; COSMIC: COSV62419195;