rs2275570

Variant names:

• chr10-110581878-A-C
• rs2275570
• NM_005445.4:c.548-45A>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.548-45A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,477,832 control chromosomes in the GnomAD database, including 12,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1215 hom., cov: 31)
  • Exomes 𝑓: 0.12 (11018 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.262
• Publications: 7 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=-0.82).
• BP6: Variant 10-110581878-A-C is Benign according to our data. Variant chr10-110581878-A-C is described in ClinVar as Benign. ClinVar VariationId is 259771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.548-45A>C		intron_variant	Intron 8 of 28	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.548-45A>C		intron_variant	Intron 8 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17722 AN: 152124 Hom.: 1211 Cov.: 31

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.152 AC: 37631 AN: 247788 AF XY: 0.149

Gnomad AFR exome AF: 0.0839

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.118 AC: 156213 AN: 1325590 Hom.: 11018 Cov.: 21 AF XY: 0.119 AC XY: 79775 AN XY: 667588

African (AFR) AF: 0.0813 AC: 2483 AN: 30534

American (AMR) AF: 0.250 AC: 11109 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3022 AN: 25272

East Asian (EAS) AF: 0.298 AC: 11606 AN: 38938

South Asian (SAS) AF: 0.179 AC: 14866 AN: 82988

European-Finnish (FIN) AF: 0.134 AC: 7063 AN: 52714

Middle Eastern (MID) AF: 0.164 AC: 904 AN: 5516

European-Non Finnish (NFE) AF: 0.0994 AC: 98348 AN: 989308

Other (OTH) AF: 0.122 AC: 6812 AN: 55846

GnomAD4 genome AF: 0.117 AC: 17748 AN: 152242 Hom.: 1215 Cov.: 31 AF XY: 0.121 AC XY: 9041 AN XY: 74426

African (AFR) AF: 0.0826 AC: 3432 AN: 41548

American (AMR) AF: 0.175 AC: 2677 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 392 AN: 3472

East Asian (EAS) AF: 0.262 AC: 1356 AN: 5180

South Asian (SAS) AF: 0.179 AC: 863 AN: 4824

European-Finnish (FIN) AF: 0.134 AC: 1419 AN: 10582

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7238 AN: 68016

Other (OTH) AF: 0.131 AC: 277 AN: 2112

Alfa AF: 0.116 Hom.: 221

Bravo AF: 0.119

Asia WGS AF: 0.214 AC: 741 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

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	-0.82
CADD	Benign	15
DANN	Benign	0.65
PhyloP100		0.26
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: rs2275570; hg19: chr10-112341636; COSMIC: COSV62418751;