rs587784428

Variant names:

• chr10-110581915-C-CTT
• rs199906378
• NM_005445.4:c.548-5_548-4dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005445.4(SMC3):​c.548-5_548-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,610,522 control chromosomes in the GnomAD database, including 1,987 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (349 hom., cov: 31)
  • Exomes 𝑓: 0.044 (1638 hom.)
• Consequence: SMC3 NM_005445.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.55
• Publications: 3 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: ClinGen, Orphanet
• Cornelia de Lange syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 10-110581915-C-CTT is Benign according to our data. Variant chr10-110581915-C-CTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 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.548-5_548-4dupTT		splice_region intron	N/A	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.548-8_548-7insTT		splice_region intron	N/A	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.548-8_548-7insTT		splice_region intron	N/A	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.566-8_566-7insTT		splice_region intron	N/A	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 8995 AN: 152064 Hom.: 348 Cov.: 31

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0651

GnomAD2 exomes AF: 0.0422 AC: 10565 AN: 250438 AF XY: 0.0424

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0273

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0449

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0442 AC: 64512 AN: 1458340 Hom.: 1638 Cov.: 31 AF XY: 0.0440 AC XY: 31927 AN XY: 725718

African (AFR) AF: 0.109 AC: 3653 AN: 33392

American (AMR) AF: 0.0295 AC: 1317 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 1053 AN: 26106

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39608

South Asian (SAS) AF: 0.0378 AC: 3255 AN: 86174

European-Finnish (FIN) AF: 0.0483 AC: 2576 AN: 53320

Middle Eastern (MID) AF: 0.0785 AC: 452 AN: 5760

European-Non Finnish (NFE) AF: 0.0445 AC: 49315 AN: 1108992

Other (OTH) AF: 0.0479 AC: 2885 AN: 60276

GnomAD4 genome AF: 0.0592 AC: 9007 AN: 152182 Hom.: 349 Cov.: 31 AF XY: 0.0584 AC XY: 4343 AN XY: 74418

African (AFR) AF: 0.106 AC: 4390 AN: 41504

American (AMR) AF: 0.0406 AC: 620 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0365 AC: 176 AN: 4822

European-Finnish (FIN) AF: 0.0503 AC: 533 AN: 10588

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0434 AC: 2951 AN: 68000

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0497 Hom.: 48

Bravo AF: 0.0601

Asia WGS AF: 0.0230 AC: 80 AN: 3476

EpiCase AF: 0.0454

EpiControl AF: 0.0445

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Cornelia de Lange syndrome 3 (1)
-	-	1	De Lange syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199906378; hg19: chr10-112341673;