NM_005445.4:c.1410-48T>C

Variant names:

• chr10-110589844-T-C
• rs3737293
• NM_005445.4:c.1410-48T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005445.4(SMC3):​c.1410-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0732 in 1,556,270 control chromosomes in the GnomAD database, including 4,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (373 hom., cov: 33)
  • Exomes 𝑓: 0.074 (4280 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.780
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-110589844-T-C is Benign according to our data. Variant chr10-110589844-T-C is described in ClinVar as Benign. ClinVar VariationId is 259767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.1410-48T>C		intron_variant	Intron 14 of 28	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.1410-48T>C		intron_variant	Intron 14 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.0626 AC: 9524 AN: 152184 Hom.: 369 Cov.: 33

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0874

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0759

Gnomad OTH AF: 0.0616

GnomAD2 exomes AF: 0.0694 AC: 17321 AN: 249638 AF XY: 0.0706

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.0449

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.0565

Gnomad NFE exome AF: 0.0713

Gnomad OTH exome AF: 0.0651

GnomAD4 exome AF: 0.0744 AC: 104419 AN: 1403968 Hom.: 4280 Cov.: 24 AF XY: 0.0749 AC XY: 52554 AN XY: 702036

African (AFR) AF: 0.0309 AC: 999 AN: 32352

American (AMR) AF: 0.0470 AC: 2097 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 1162 AN: 25718

East Asian (EAS) AF: 0.140 AC: 5525 AN: 39364

South Asian (SAS) AF: 0.0800 AC: 6803 AN: 85030

European-Finnish (FIN) AF: 0.0567 AC: 3023 AN: 53272

Middle Eastern (MID) AF: 0.0354 AC: 194 AN: 5486

European-Non Finnish (NFE) AF: 0.0757 AC: 80232 AN: 1059738

Other (OTH) AF: 0.0751 AC: 4384 AN: 58364

GnomAD4 genome AF: 0.0626 AC: 9537 AN: 152302 Hom.: 373 Cov.: 33 AF XY: 0.0619 AC XY: 4608 AN XY: 74466

African (AFR) AF: 0.0318 AC: 1320 AN: 41574

American (AMR) AF: 0.0569 AC: 870 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3466

East Asian (EAS) AF: 0.142 AC: 736 AN: 5190

South Asian (SAS) AF: 0.0877 AC: 423 AN: 4824

European-Finnish (FIN) AF: 0.0605 AC: 642 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0759 AC: 5165 AN: 68016

Other (OTH) AF: 0.0666 AC: 141 AN: 2116

Alfa AF: 0.0668 Hom.: 799

Bravo AF: 0.0605

Asia WGS AF: 0.135 AC: 470 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.7
DANN	Benign	0.36
PhyloP100		0.78
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: rs3737293; hg19: chr10-112349602; COSMIC: COSV62419034;