rs199906378

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_005445.4(SMC3):c.548-5_548-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,610,522 control chromosomes in the GnomAD database, including 1,987 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 349 hom., cov: 31)

Exomes 𝑓: 0.044 ( 1638 hom. )

Consequence

SMC3
NM_005445.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.55

Publications

3 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 -16 ACMG points.

BP6

Variant 10-110581915-C-CTT is Benign according to our data. Variant chr10-110581915-C-CTT is described in ClinVar as [Likely_benign]. Clinvar id is 159989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4 link	c.548-5_548-4dupTT		splice_region_variant, intron_variant	Intron 8 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.548-8_548-7insTT		splice_region_variant, intron_variant	Intron 8 of 28	1	NM_005445.4	ENSP00000354720.5		Q9UQE7

Frequencies

GnomAD3 genomes

AF:

0.0592

AC:

8995

AN:

152064

Hom.:

348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0406

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0363

Gnomad FIN

AF:

0.0503

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0434

Gnomad OTH

AF:

0.0651

GnomAD2 exomes

AF:

0.0422

AC:

10565

AN:

250438

AF XY:

0.0424

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.0273

Gnomad ASJ exome

AF:

0.0416

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0480

Gnomad NFE exome

AF:

0.0449

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0442

AC:

64512

AN:

1458340

Hom.:

1638

Cov.:

AF XY:

0.0440

AC XY:

31927

AN XY:

725718

show subpopulations

African (AFR)

AF:

0.109

AC:

3653

AN:

33392

American (AMR)

AF:

0.0295

AC:

1317

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0403

AC:

1053

AN:

26106

East Asian (EAS)

AF:

0.000151

AC:

AN:

39608

South Asian (SAS)

AF:

0.0378

AC:

3255

AN:

86174

European-Finnish (FIN)

AF:

0.0483

AC:

2576

AN:

53320

Middle Eastern (MID)

AF:

0.0785

AC:

452

AN:

5760

European-Non Finnish (NFE)

AF:

0.0445

AC:

49315

AN:

1108992

Other (OTH)

AF:

0.0479

AC:

2885

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

2720

5440

8161

10881

13601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1864

3728

5592

7456

9320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0592

AC:

9007

AN:

152182

Hom.:

349

Cov.:

AF XY:

0.0584

AC XY:

4343

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.106

AC:

4390

AN:

41504

American (AMR)

AF:

0.0406

AC:

620

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

151

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.0365

AC:

176

AN:

4822

European-Finnish (FIN)

AF:

0.0503

AC:

533

AN:

10588

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0434

AC:

2951

AN:

68000

Other (OTH)

AF:

0.0644

AC:

136

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

436

873

1309

1746

2182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0497

Hom.:

Bravo

AF:

0.0601

Asia WGS

AF:

0.0230

AC:

AN:

3476

EpiCase

AF:

0.0454

EpiControl

AF:

0.0445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 02, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 02, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 05, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cornelia de Lange syndrome 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

De Lange syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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