rs2297104

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006306.4(SMC1A):c.2197-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,160,911 control chromosomes in the GnomAD database, including 344 homozygotes. There are 2,792 hemizygotes in GnomAD. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 30 hom., 338 hem., cov: 22)

Exomes 𝑓: 0.0081 ( 314 hom. 2454 hem. )

Consequence

SMC1A
NM_006306.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0008819

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.23

Variant links:

Genes affected

SMC1A (HGNC:11111): (structural maintenance of chromosomes 1A) Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

SMC1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant X-53403898-A-G is Benign according to our data. Variant chrX-53403898-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 95365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53403898-A-G is described in Lovd as [Benign]. Variant chrX-53403898-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1A	NM_006306.4 linkuse as main transcript	c.2197-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000322213.9
SMC1A	NM_001281463.1 linkuse as main transcript	c.2131-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
SMC1A	ENST00000322213.9 linkuse as main transcript	c.2197-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_006306.4	P1
SMC1A	ENST00000375340.10 linkuse as main transcript	c.2131-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1
SMC1A	ENST00000674590.1 linkuse as main transcript	c.1429-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SMC1A	ENST00000675504.1 linkuse as main transcript	c.2131-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00984

AC:

1100

AN:

111811

Hom.:

Cov.:

AF XY:

0.00986

AC XY:

335

AN XY:

33973

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0547

Gnomad ASJ

AF:

0.0162

Gnomad EAS

AF:

0.0742

Gnomad SAS

AF:

0.00440

Gnomad FIN

AF:

0.000996

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.000826

Gnomad OTH

AF:

0.0188

GnomAD3 exomes

AF:

0.0249

AC:

4560

AN:

183248

Hom.:

208

AF XY:

0.0181

AC XY:

1229

AN XY:

67716

show subpopulations

Gnomad AFR exome

AF:

0.00433

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.0677

Gnomad SAS exome

AF:

0.00430

Gnomad FIN exome

AF:

0.00132

Gnomad NFE exome

AF:

0.00169

Gnomad OTH exome

AF:

0.0161

GnomAD4 exome

AF:

0.00809

AC:

8484

AN:

1049047

Hom.:

314

Cov.:

AF XY:

0.00769

AC XY:

2454

AN XY:

319309

show subpopulations

Gnomad4 AFR exome

AF:

0.00243

Gnomad4 AMR exome

AF:

0.111

Gnomad4 ASJ exome

AF:

0.0129

Gnomad4 EAS exome

AF:

0.0986

Gnomad4 SAS exome

AF:

0.00466

Gnomad4 FIN exome

AF:

0.00141

Gnomad4 NFE exome

AF:

0.000600

Gnomad4 OTH exome

AF:

0.0123

GnomAD4 genome

AF:

0.00983

AC:

1100

AN:

111864

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

338

AN XY:

34036

show subpopulations

Gnomad4 AFR

AF:

0.00431

Gnomad4 AMR

AF:

0.0549

Gnomad4 ASJ

AF:

0.0162

Gnomad4 EAS

AF:

0.0739

Gnomad4 SAS

AF:

0.00368

Gnomad4 FIN

AF:

0.000996

Gnomad4 NFE

AF:

0.000826

Gnomad4 OTH

AF:

0.0192

Alfa

AF:

0.00860

Hom.:

Bravo

AF:

0.0158

EpiCase

AF:

0.000763

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2013	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2015

This alteration is classified as 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. -

Congenital muscular hypertrophy-cerebral syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

De Lange syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

Cadd

Benign

Dann

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00088

dbscSNV1_RF

Benign

0.098

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over