10-110567743-C-A

Variant names:

• chr10-110567743-C-A
• rs376252081
• NM_005445.4:c.-74C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005445.4(SMC3):​c.-74C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,577,144 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: SMC3 NM_005445.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.765
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00123 (188/152348) while in subpopulation AMR AF = 0.00333 (51/15310). AF 95% confidence interval is 0.0026. There are 0 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 188 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.-74C>A		5_prime_UTR_variant	Exon 1 of 29	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.-74C>A		5_prime_UTR_variant	Exon 1 of 29	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 188 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00132 AC: 1885 AN: 1424796 Hom.: 3 Cov.: 26 AF XY: 0.00135 AC XY: 960 AN XY: 710646

African (AFR) AF: 0.000153 AC: 5 AN: 32758

American (AMR) AF: 0.00144 AC: 64 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.00128 AC: 33 AN: 25720

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39498

South Asian (SAS) AF: 0.000984 AC: 84 AN: 85388

European-Finnish (FIN) AF: 0.000781 AC: 41 AN: 52498

Middle Eastern (MID) AF: 0.00168 AC: 9 AN: 5342

European-Non Finnish (NFE) AF: 0.00144 AC: 1552 AN: 1080126

Other (OTH) AF: 0.00162 AC: 96 AN: 59094

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152348 Hom.: 0 Cov.: 34 AF XY: 0.00144 AC XY: 107 AN XY: 74496

African (AFR) AF: 0.000240 AC: 10 AN: 41584

American (AMR) AF: 0.00333 AC: 51 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000265 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.85
PhyloP100		0.77
PromoterAI		0.045	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=298/2	polymorphism

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: rs376252081; hg19: chr10-112327501;