rs146433240

Variant names:

• chr10-110577477-A-G
• rs146433240
• NM_005445.4:c.255A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005445.4(SMC3):​c.255A>G​(p.Ser85Ser) 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:8
• Conservation: PhyloP100: -1.12
• Publications: 6 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 -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 VariationId is 159980.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 499 AD gene.

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.255A>G	p.Ser85Ser	synonymous	Exon 5 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.255A>G	p.Ser85Ser	synonymous	Exon 5 of 29	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.255A>G	p.Ser85Ser	synonymous	Exon 5 of 29	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.273A>G	p.Ser91Ser	synonymous	Exon 5 of 29	ENSP00000636435.1

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

GnomAD2 exomes AF: 0.00354 AC: 890 AN: 251124 AF XY: 0.00359

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 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

African (AFR) AF: 0.000988 AC: 33 AN: 33404

American (AMR) AF: 0.00479 AC: 214 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26096

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39560

South Asian (SAS) AF: 0.000963 AC: 83 AN: 86158

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53314

Middle Eastern (MID) AF: 0.00869 AC: 50 AN: 5754

European-Non Finnish (NFE) AF: 0.00617 AC: 6847 AN: 1109332

Other (OTH) AF: 0.00641 AC: 386 AN: 60254

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

African (AFR) AF: 0.00130 AC: 54 AN: 41598

American (AMR) AF: 0.00425 AC: 65 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00522 AC: 355 AN: 68004

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.7
DANN	Benign	0.71
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism

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: rs146433240; hg19: chr10-112337235;