NM_005445.4:c.724-6dupT

Variant names:

• chr10-110582548-G-GT
• rs11380915
• NM_005445.4:c.724-6dupT

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.724-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.054 in 1,590,282 control chromosomes in the GnomAD database, including 3,871 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1389 hom., cov: 30)
  • Exomes 𝑓: 0.049 (2482 hom.)
• Consequence: SMC3 NM_005445.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.141
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 10-110582548-G-GT is Benign according to our data. Variant chr10-110582548-G-GT is described in ClinVar as Benign. ClinVar VariationId is 159991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 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.724-6dupT		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.724-14_724-13insT		intron	N/A	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.724-14_724-13insT		intron	N/A	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.742-14_742-13insT		intron	N/A	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15237 AN: 151864 Hom.: 1385 Cov.: 30

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.0598

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0361

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.0541 AC: 13285 AN: 245618 AF XY: 0.0512

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0385

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.000446

Gnomad FIN exome AF: 0.0479

Gnomad NFE exome AF: 0.0469

Gnomad OTH exome AF: 0.0595

GnomAD4 exome AF: 0.0491 AC: 70654 AN: 1438300 Hom.: 2482 Cov.: 28 AF XY: 0.0483 AC XY: 34646 AN XY: 716932

African (AFR) AF: 0.251 AC: 8207 AN: 32754

American (AMR) AF: 0.0414 AC: 1843 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.0405 AC: 1054 AN: 26010

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39486

South Asian (SAS) AF: 0.0381 AC: 3259 AN: 85470

European-Finnish (FIN) AF: 0.0482 AC: 2568 AN: 53298

Middle Eastern (MID) AF: 0.0931 AC: 529 AN: 5680

European-Non Finnish (NFE) AF: 0.0455 AC: 49692 AN: 1091472

Other (OTH) AF: 0.0587 AC: 3495 AN: 59564

GnomAD4 genome AF: 0.100 AC: 15266 AN: 151982 Hom.: 1389 Cov.: 30 AF XY: 0.0979 AC XY: 7274 AN XY: 74326

African (AFR) AF: 0.246 AC: 10190 AN: 41416

American (AMR) AF: 0.0597 AC: 912 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0364 AC: 175 AN: 4812

European-Finnish (FIN) AF: 0.0503 AC: 532 AN: 10578

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0446 AC: 3029 AN: 67946

Other (OTH) AF: 0.102 AC: 215 AN: 2110

Alfa AF: 0.0311 Hom.: 21

Bravo AF: 0.108

Asia WGS AF: 0.0330 AC: 115 AN: 3478

ClinVar

ClinVar submissions

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	De Lange syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11380915; hg19: chr10-112342306; COSMIC: COSV100699777; COSMIC: COSV100699777;