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: PanelApp Australia, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005445.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	NM_005445.4	MANE Select	c.1365T>C	p.Tyr455Tyr	synonymous	Exon 14 of 29	NP_005436.1	Q9UQE7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	ENST00000361804.5	TSL:1 MANE Select	c.1365T>C	p.Tyr455Tyr	synonymous	Exon 14 of 29	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.1389T>C	p.Tyr463Tyr	synonymous	Exon 14 of 29	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.1383T>C	p.Tyr461Tyr	synonymous	Exon 14 of 29	ENSP00000636435.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Cornelia de Lange syndrome 3 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;