rs11195199

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005445.4(SMC3):c.970-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,608,740 control chromosomes in the GnomAD database, including 12,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1221 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11504 hom. )

Consequence

SMC3
NM_005445.4 splice_region, intron

Scores

Splicing: ADA: 0.0001165

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.25

Publications

15 publications found

Variant links:

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)

SMC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 10-110583833-G-A is Benign according to our data. Variant chr10-110583833-G-A is described in ClinVar as [Benign]. Clinvar id is 159992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4 link	c.970-8G>A		splice_region_variant, intron_variant	Intron 11 of 28	ENST00000361804.5	NP_005436.1	Q9UQE7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5 link	c.970-8G>A		splice_region_variant, intron_variant	Intron 11 of 28	1	NM_005445.4	ENSP00000354720.5		Q9UQE7

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17725

AN:

151818

Hom.:

1217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0827

Gnomad AMI

AF:

0.0538

Gnomad AMR

AF:

0.175

Gnomad ASJ

AF:

0.113

Gnomad EAS

AF:

0.263

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.130

GnomAD2 exomes

AF:

0.151

AC:

37473

AN:

248774

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.0836

Gnomad AMR exome

AF:

0.261

Gnomad ASJ exome

AF:

0.122

Gnomad EAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.136

Gnomad NFE exome

AF:

0.109

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.115

AC:

167743

AN:

1456804

Hom.:

11504

Cov.:

AF XY:

0.117

AC XY:

84795

AN XY:

724704

show subpopulations

African (AFR)

AF:

0.0808

AC:

2689

AN:

33274

American (AMR)

AF:

0.248

AC:

10983

AN:

44252

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3098

AN:

26034

East Asian (EAS)

AF:

0.298

AC:

11761

AN:

39492

South Asian (SAS)

AF:

0.177

AC:

15163

AN:

85472

European-Finnish (FIN)

AF:

0.134

AC:

7146

AN:

53176

Middle Eastern (MID)

AF:

0.163

AC:

937

AN:

5746

European-Non Finnish (NFE)

AF:

0.0980

AC:

108666

AN:

1109190

Other (OTH)

AF:

0.121

AC:

7300

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

6789

13578

20368

27157

33946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.117

AC:

17751

AN:

151936

Hom.:

1221

Cov.:

AF XY:

0.122

AC XY:

9055

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.0828

AC:

3432

AN:

41462

American (AMR)

AF:

0.175

AC:

2672

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

391

AN:

3470

East Asian (EAS)

AF:

0.263

AC:

1361

AN:

5172

South Asian (SAS)

AF:

0.179

AC:

860

AN:

4810

European-Finnish (FIN)

AF:

0.136

AC:

1433

AN:

10518

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.106

AC:

7232

AN:

67920

Other (OTH)

AF:

0.131

AC:

276

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

792

1584

2375

3167

3959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.108

Hom.:

1152

Bravo

AF:

0.119

Asia WGS

AF:

0.213

AC:

740

AN:

3478

EpiCase

AF:

0.104

EpiControl

AF:

0.109

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 2017

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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cornelia de Lange syndrome 3

Benign:2

Jan 13, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.0

(source)

DANN

Benign

0.42

PhyloP100

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.0

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

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rs11195199

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over