10-110568767-CTTTTT-CTTTTTTT

Variant names:

• chr10-110568767-C-CTT
• rs35132779
• NM_005445.4:c.16-159_16-158dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005445.4(SMC3):​c.16-159_16-158dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 143,192 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0047 (2 hom., cov: 27)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.208
• Publications: 0 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00467 (669/143192) while in subpopulation AFR AF = 0.00738 (289/39166). AF 95% confidence interval is 0.00668. There are 2 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 669 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.16-159_16-158dupTT		intron_variant	Intron 1 of 28	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.16-171_16-170insTT		intron_variant	Intron 1 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 668 AN: 143140 Hom.: 2 Cov.: 27

Gnomad AFR AF: 0.00737

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00160

Gnomad ASJ AF: 0.00418

Gnomad EAS AF: 0.000797

Gnomad SAS AF: 0.000876

Gnomad FIN AF: 0.00457

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00436

Gnomad OTH AF: 0.00513

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00467 AC: 669 AN: 143192 Hom.: 2 Cov.: 27 AF XY: 0.00490 AC XY: 341 AN XY: 69548

African (AFR) AF: 0.00738 AC: 289 AN: 39166

American (AMR) AF: 0.00160 AC: 23 AN: 14412

Ashkenazi Jewish (ASJ) AF: 0.00418 AC: 14 AN: 3348

East Asian (EAS) AF: 0.000799 AC: 4 AN: 5004

South Asian (SAS) AF: 0.000880 AC: 4 AN: 4546

European-Finnish (FIN) AF: 0.00457 AC: 39 AN: 8528

Middle Eastern (MID) AF: 0.00365 AC: 1 AN: 274

European-Non Finnish (NFE) AF: 0.00437 AC: 284 AN: 65056

Other (OTH) AF: 0.00510 AC: 10 AN: 1960

Alfa AF: 0.000885 Hom.: 57

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs35132779; hg19: chr10-112328525;