rs146433240

Positions:

• chr10-110577477-A-G
• chr10-110577477-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005445.4(SMC3):​c.255A>G​(p.Ser85=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,610,920 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S85S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (35 hom.)
• Consequence: SMC3 NM_005445.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.12

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-110577477-A-G is Benign according to our data. Variant chr10-110577477-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159980.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=4}. Variant chr10-110577477-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00328 (499/152330) while in subpopulation NFE AF= 0.00522 (355/68004). AF 95% confidence interval is 0.00477. There are 0 homozygotes in gnomad4. There are 220 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 499 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC3	NM_005445.4	c.255A>G	p.Ser85=	synonymous_variant	5/29	ENST00000361804.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC3	ENST00000361804.5	c.255A>G	p.Ser85=	synonymous_variant	5/29	1	NM_005445.4	P1

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00354 AC: 890 AN: 251124 Hom.: 4 AF XY: 0.00359 AC XY: 487 AN XY: 135748

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00568

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00524 AC: 7638 AN: 1458590 Hom.: 35 Cov.: 29 AF XY: 0.00501 AC XY: 3640 AN XY: 725904

Gnomad4 AFR exome AF: 0.000988

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000963

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00617

Gnomad4 OTH exome AF: 0.00641

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00295 AC XY: 220 AN XY: 74498

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.00382

Asia WGS AF: 0.000578 AC: 2 AN: 3472

EpiCase AF: 0.00583

EpiControl AF: 0.00747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cornelia de Lange syndrome 3 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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	Invitae	Jan 27, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SMC3: BP4, BP7, BS1, BS2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 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	-0.77
CADD	Benign	3.7
DANN	Benign	0.71

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: rs146433240; hg19: chr10-112337235;