chr10-110578619-T-C

Variant names:

• chr10-110578619-T-C
• rs78663177
• NM_005445.4:c.351-9T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005445.4(SMC3):​c.351-9T>C variant causes a intron change. The variant allele was found at a frequency of 0.0456 in 1,598,230 control chromosomes in the GnomAD database, including 1,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (353 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1621 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Scores: Splicing: ADA: 0.7622
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.07
• 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 10-110578619-T-C is Benign according to our data. Variant chr10-110578619-T-C is described in ClinVar as Benign. ClinVar VariationId is 159986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 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.351-9T>C		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.351-9T>C		intron	N/A	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.351-9T>C		intron	N/A	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.369-9T>C		intron	N/A	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 9014 AN: 152172 Hom.: 352 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0341

Gnomad FIN AF: 0.0504

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0645

GnomAD2 exomes AF: 0.0417 AC: 9831 AN: 235588 AF XY: 0.0416

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0271

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.000337

Gnomad FIN exome AF: 0.0482

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0441 AC: 63790 AN: 1445940 Hom.: 1621 Cov.: 29 AF XY: 0.0438 AC XY: 31480 AN XY: 718574

African (AFR) AF: 0.110 AC: 3654 AN: 33238

American (AMR) AF: 0.0295 AC: 1289 AN: 43738

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 1046 AN: 25906

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39536

South Asian (SAS) AF: 0.0353 AC: 2981 AN: 84456

European-Finnish (FIN) AF: 0.0484 AC: 2559 AN: 52824

Middle Eastern (MID) AF: 0.0780 AC: 445 AN: 5702

European-Non Finnish (NFE) AF: 0.0445 AC: 48959 AN: 1100826

Other (OTH) AF: 0.0477 AC: 2851 AN: 59714

GnomAD4 genome AF: 0.0593 AC: 9027 AN: 152290 Hom.: 353 Cov.: 32 AF XY: 0.0583 AC XY: 4343 AN XY: 74462

African (AFR) AF: 0.106 AC: 4420 AN: 41540

American (AMR) AF: 0.0406 AC: 621 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0344 AC: 166 AN: 4828

European-Finnish (FIN) AF: 0.0504 AC: 535 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0434 AC: 2949 AN: 68026

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0518 Hom.: 165

Bravo AF: 0.0603

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.87
PhyloP100		7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Benign	0.42
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: rs78663177; hg19: chr10-112338377;