rs75323904

Variant names:

• chr10-110589664-T-C
• rs75323904
• NM_005445.4:c.1365T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005445.4(SMC3):​c.1365T>C​(p.Tyr455Tyr) 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
• Publications: 11 publications found

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]

SMC3 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 159967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.1365T>C	p.Tyr455Tyr	synonymous_variant	Exon 14 of 29	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.1365T>C	p.Tyr455Tyr	synonymous_variant	Exon 14 of 29	1	NM_005445.4	ENSP00000354720.5

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

GnomAD2 exomes AF: 0.0422 AC: 10552 AN: 249876 AF XY: 0.0424

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 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

African (AFR) AF: 0.110 AC: 3653 AN: 33338

American (AMR) AF: 0.0295 AC: 1317 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 1050 AN: 26066

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39656

South Asian (SAS) AF: 0.0378 AC: 3250 AN: 86020

European-Finnish (FIN) AF: 0.0483 AC: 2579 AN: 53374

Middle Eastern (MID) AF: 0.0783 AC: 447 AN: 5706

European-Non Finnish (NFE) AF: 0.0444 AC: 49230 AN: 1108490

Other (OTH) AF: 0.0479 AC: 2885 AN: 60228

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

African (AFR) AF: 0.106 AC: 4410 AN: 41534

American (AMR) AF: 0.0404 AC: 618 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0365 AC: 176 AN: 4822

European-Finnish (FIN) AF: 0.0506 AC: 537 AN: 10616

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0434 AC: 2954 AN: 68006

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0512 Hom.: 143

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

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cornelia de Lange syndrome 3 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Apr 19, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.5
DANN	Benign	0.42
PhyloP100		-0.044
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75323904; hg19: chr10-112349422;