rs2297104

Positions:

• chrX-53403898-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006306.4(SMC1A):​c.2197-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 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, intron
• Scores: Splicing: ADA: 0.0008819
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.23

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]

ACMG classification

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	Protein	UniProt
SMC1A	NM_006306.4	c.2197-5T>C		splice_region_variant, intron_variant		ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.2131-5T>C		splice_region_variant, intron_variant			NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.2197-5T>C		splice_region_variant, intron_variant		1	NM_006306.4	ENSP00000323421.3
SMC1A	ENST00000375340.10	c.2131-5T>C		splice_region_variant, intron_variant		1		ENSP00000364489.7
SMC1A	ENST00000675504.1	c.2131-5T>C		splice_region_variant, intron_variant				ENSP00000502524.1
SMC1A	ENST00000674590.1	c.1429-5T>C		splice_region_variant, intron_variant				ENSP00000502626.1

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1100 AN: 111811 Hom.: 31 Cov.: 22 AF XY: 0.00986 AC XY: 335 AN XY: 33973

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

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.: 26 AF XY: 0.00769 AC XY: 2454 AN XY: 319309

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.: 30 Cov.: 22 AF XY: 0.00993 AC XY: 338 AN XY: 34036

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.: 65

Bravo AF: 0.0158

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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	Jul 03, 2024	- -
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	Eurofins Ntd Llc (ga)	Jul 16, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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	11
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

Other links and lift over

dbSNP: rs2297104; hg19: chrX-53430830; COSMIC: COSV59132427; COSMIC: COSV59132427;