rs142611198

chrX-53381075-G-AchrX-53381075-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006306.4(SMC1A):c.3450C>T(p.Ala1150=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,205,088 control chromosomes in the GnomAD database, including 5 homozygotes. There are 651 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1150A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., 58 hem., cov: 22)
  • Exomes 𝑓: 0.0016 (3 hom. 593 hem.)
• Consequence: SMC1A NM_006306.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.326

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-53381075-G-A is Benign according to our data. Variant chrX-53381075-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 159957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53381075-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.326 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00177 (196/110486) while in subpopulation AMR AF= 0.00585 (61/10428). AF 95% confidence interval is 0.00467. There are 2 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1A	NM_006306.4	c.3450C>T	p.Ala1150=	synonymous_variant	23/25	ENST00000322213.9
SMC1A	NM_001281463.1	c.3384C>T	p.Ala1128=	synonymous_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC1A	ENST00000322213.9	c.3450C>T	p.Ala1150=	synonymous_variant	23/25	1	NM_006306.4	P1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 196 AN: 110433 Hom.: 2 Cov.: 22 AF XY: 0.00178 AC XY: 58 AN XY: 32617

Gnomad AFR AF: 0.000264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00586

Gnomad ASJ AF: 0.00456

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00203

GnomAD3 exomes AF: 0.00147 AC: 269 AN: 183171 Hom.: 1 AF XY: 0.00166 AC XY: 112 AN XY: 67649

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00187

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00126

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00161 AC: 1763 AN: 1094602 Hom.: 3 Cov.: 30 AF XY: 0.00165 AC XY: 593 AN XY: 360050

Gnomad4 AFR exome AF: 0.000266

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.000247

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00177 AC: 196 AN: 110486 Hom.: 2 Cov.: 22 AF XY: 0.00177 AC XY: 58 AN XY: 32680

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.00585

Gnomad4 ASJ AF: 0.00456

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00200

Alfa AF: 0.00207 Hom.: 15

Bravo AF: 0.00171

EpiCase AF: 0.00294

EpiControl AF: 0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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)	Feb 02, 2015	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	- -

Congenital muscular hypertrophy-cerebral syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2016

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. -

Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	6.7
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs142611198; hg19: chrX-53407996;