10-110567718-C-A

Variant names:

• chr10-110567718-C-A
• rs148267784
• NM_005445.4:c.-99C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_005445.4(SMC3):​c.-99C>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 0.0171 in 1,451,596 control chromosomes in the GnomAD database, including 278 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 0.014 (21 hom., cov: 34)
  • Exomes 𝑓: 0.017 (257 hom.)
• Consequence: SMC3 NM_005445.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.201
• Publications: 1 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.014 (2133/152338) while in subpopulation AMR AF = 0.041 (628/15304). AF 95% confidence interval is 0.0384. There are 21 homozygotes in GnomAd4. There are 1067 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2133 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.-99C>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.-99C>A		5_prime_UTR_variant	Exon 1 of 29	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2127 AN: 152220 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.0174 AC: 22670 AN: 1299258 Hom.: 257 Cov.: 18 AF XY: 0.0176 AC XY: 11473 AN XY: 653032

African (AFR) AF: 0.00421 AC: 127 AN: 30136

American (AMR) AF: 0.0441 AC: 1859 AN: 42176

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 415 AN: 24244

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38720

South Asian (SAS) AF: 0.0220 AC: 1801 AN: 81724

European-Finnish (FIN) AF: 0.00558 AC: 288 AN: 51642

Middle Eastern (MID) AF: 0.0342 AC: 156 AN: 4558

European-Non Finnish (NFE) AF: 0.0176 AC: 17092 AN: 971420

Other (OTH) AF: 0.0170 AC: 927 AN: 54638

GnomAD4 genome AF: 0.0140 AC: 2133 AN: 152338 Hom.: 21 Cov.: 34 AF XY: 0.0143 AC XY: 1067 AN XY: 74488

African (AFR) AF: 0.00327 AC: 136 AN: 41590

American (AMR) AF: 0.0410 AC: 628 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5172

South Asian (SAS) AF: 0.0192 AC: 93 AN: 4834

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10630

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1113 AN: 68018

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.00368 Hom.: 0

Bravo AF: 0.0161

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cornelia de Lange syndrome 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		0.20
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	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: rs148267784; hg19: chr10-112327476;