rs147404470

Positions:

• chr10-110596441-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005445.4(SMC3):​c.2007T>C​(p.Tyr669Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,614,042 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (36 hom.)
• Consequence: SMC3 NM_005445.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0640

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-110596441-T-C is Benign according to our data. Variant chr10-110596441-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 159971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110596441-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.064 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00479 (729/152270) while in subpopulation NFE AF= 0.007 (476/68016). AF 95% confidence interval is 0.00648. There are 1 homozygotes in gnomad4. There are 358 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 729 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC3	NM_005445.4	c.2007T>C	p.Tyr669Tyr	synonymous_variant	19/29	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.2007T>C	p.Tyr669Tyr	synonymous_variant	19/29	1	NM_005445.4	ENSP00000354720.5
SMC3	ENST00000684988.1	n.2652T>C		non_coding_transcript_exon_variant	17/25
SMC3	ENST00000692792.1	n.2126T>C		non_coding_transcript_exon_variant	19/19

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 729 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00700

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00491 AC: 1234 AN: 251286 Hom.: 4 AF XY: 0.00496 AC XY: 674 AN XY: 135806

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00984

Gnomad NFE exome AF: 0.00720

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00661 AC: 9656 AN: 1461772 Hom.: 36 Cov.: 31 AF XY: 0.00638 AC XY: 4640 AN XY: 727178

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00764

Gnomad4 OTH exome AF: 0.00541

GnomAD4 genome AF: 0.00479 AC: 729 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74460

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00700

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00605 Hom.: 0

Bravo AF: 0.00406

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

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	Genetic Services Laboratory, University of Chicago	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2018	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SMC3: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2020	- -

Cornelia de Lange syndrome 3 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.6
DANN	Benign	0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs147404470; hg19: chr10-112356199;