10-110567743-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. Variant has been reported in ClinVar as Likely benign (★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 10-110567743-C-A is Benign according to our data. Variant chr10-110567743-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 298761.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 188 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC3	NM_005445.4	c.-74C>A		5_prime_UTR_variant	1/29	ENST00000361804.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC3	ENST00000361804.5	c.-74C>A		5_prime_UTR_variant	1/29	1	NM_005445.4	P1
SMC3	ENST00000684988.1	n.60C>A		non_coding_transcript_exon_variant	1/25
SMC3	ENST00000691297.1	n.60C>A		non_coding_transcript_exon_variant	1/17
SMC3	ENST00000691527.1	n.17C>A		non_coding_transcript_exon_variant	1/16

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

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.00128

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000984

Gnomad4 FIN exome AF: 0.000781

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00162

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

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00284

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs376252081; hg19: chr10-112327501;