10-110568892-A-AT

Variant names:

• chr10-110568892-A-AT
• rs149144103
• NM_005445.4:c.16-38dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005445.4(SMC3):​c.16-38dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0656 in 1,103,746 control chromosomes in the GnomAD database, including 4,252 homozygotes. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.12 (1873 hom., cov: 30)
  • Exomes 𝑓: 0.057 (2379 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.376
• 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 -10 ACMG points.

• BP6: Variant 10-110568892-A-AT is Benign according to our data. Variant chr10-110568892-A-AT is described in ClinVar as [Benign]. Clinvar id is 1233049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.16-38dupT		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.16-46_16-45insT		intron_variant	Intron 1 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18059 AN: 151678 Hom.: 1861 Cov.: 30

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0453

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.0476

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0510

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.0608 AC: 14322 AN: 235420 AF XY: 0.0558

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.0882

Gnomad ASJ exome AF: 0.0384

Gnomad EAS exome AF: 0.0246

Gnomad FIN exome AF: 0.0538

Gnomad NFE exome AF: 0.0457

Gnomad OTH exome AF: 0.0585

GnomAD4 exome AF: 0.0570 AC: 54240 AN: 951952 Hom.: 2379 Cov.: 13 AF XY: 0.0554 AC XY: 27496 AN XY: 496070

African (AFR) AF: 0.273 AC: 6279 AN: 23022

American (AMR) AF: 0.109 AC: 4746 AN: 43700

Ashkenazi Jewish (ASJ) AF: 0.0419 AC: 960 AN: 22926

East Asian (EAS) AF: 0.0408 AC: 1526 AN: 37360

South Asian (SAS) AF: 0.0464 AC: 3506 AN: 75486

European-Finnish (FIN) AF: 0.0586 AC: 3078 AN: 52512

Middle Eastern (MID) AF: 0.0954 AC: 453 AN: 4748

European-Non Finnish (NFE) AF: 0.0471 AC: 30581 AN: 648762

Other (OTH) AF: 0.0716 AC: 3111 AN: 43436

GnomAD4 genome AF: 0.119 AC: 18115 AN: 151794 Hom.: 1873 Cov.: 30 AF XY: 0.118 AC XY: 8726 AN XY: 74186

African (AFR) AF: 0.278 AC: 11474 AN: 41346

American (AMR) AF: 0.107 AC: 1634 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0453 AC: 157 AN: 3464

East Asian (EAS) AF: 0.0336 AC: 174 AN: 5174

South Asian (SAS) AF: 0.0479 AC: 230 AN: 4802

European-Finnish (FIN) AF: 0.0612 AC: 643 AN: 10510

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0510 AC: 3463 AN: 67924

Other (OTH) AF: 0.119 AC: 250 AN: 2100

Alfa AF: 0.0264 Hom.: 24

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
BranchPoint Hunter		1.0
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: rs149144103; hg19: chr10-112328650;