rs11195200

Variant names:

• chr10-110584165-T-C
• rs11195200
• NM_005445.4:c.1092-18T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005445.4(SMC3):​c.1092-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,609,840 control chromosomes in the GnomAD database, including 12,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1221 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11583 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.18
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-110584165-T-C is Benign according to our data. Variant chr10-110584165-T-C is described in ClinVar as Benign. ClinVar VariationId is 259765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 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.1092-18T>C		intron	N/A	NP_005436.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	ENST00000361804.5	TSL:1 MANE Select	c.1092-18T>C		intron	N/A	ENSP00000354720.5
	SMC3	ENST00000918257.1		c.1116-18T>C		intron	N/A	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.1110-18T>C		intron	N/A	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17735 AN: 152142 Hom.: 1217 Cov.: 32

Gnomad AFR AF: 0.0826

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.151 AC: 38019 AN: 250984 AF XY: 0.149

Gnomad AFR exome AF: 0.0842

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.247

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.116 AC: 168400 AN: 1457580 Hom.: 11583 Cov.: 32 AF XY: 0.117 AC XY: 85145 AN XY: 725386

African (AFR) AF: 0.0810 AC: 2706 AN: 33402

American (AMR) AF: 0.250 AC: 11170 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3108 AN: 26094

East Asian (EAS) AF: 0.297 AC: 11789 AN: 39644

South Asian (SAS) AF: 0.179 AC: 15411 AN: 86164

European-Finnish (FIN) AF: 0.134 AC: 7166 AN: 53416

Middle Eastern (MID) AF: 0.163 AC: 939 AN: 5758

European-Non Finnish (NFE) AF: 0.0982 AC: 108785 AN: 1108116

Other (OTH) AF: 0.122 AC: 7326 AN: 60268

GnomAD4 genome AF: 0.117 AC: 17761 AN: 152260 Hom.: 1221 Cov.: 32 AF XY: 0.122 AC XY: 9052 AN XY: 74450

African (AFR) AF: 0.0827 AC: 3435 AN: 41548

American (AMR) AF: 0.175 AC: 2671 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 392 AN: 3472

East Asian (EAS) AF: 0.262 AC: 1360 AN: 5182

South Asian (SAS) AF: 0.179 AC: 865 AN: 4830

European-Finnish (FIN) AF: 0.135 AC: 1430 AN: 10614

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7237 AN: 68014

Other (OTH) AF: 0.131 AC: 277 AN: 2112

Alfa AF: 0.112 Hom.: 544

Bravo AF: 0.119

Asia WGS AF: 0.214 AC: 741 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.43
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs11195200; hg19: chr10-112343923; COSMIC: COSV62421733; COSMIC: COSV62421733;