rs1556886124

Variant names:

• chrX-53383124-G-A
• rs1556886124
• NM_006306.4:c.3103C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006306.4(SMC1A):​c.3103C>T​(p.Arg1035*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMC1A NM_006306.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.14

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53383124-G-A is Pathogenic according to our data. Variant chrX-53383124-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 532569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.3103C>T	p.Arg1035*	stop_gained	Exon 20 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.3037C>T	p.Arg1013*	stop_gained	Exon 21 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.3103C>T	p.Arg1035*	stop_gained	Exon 20 of 25	1	NM_006306.4	ENSP00000323421.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:2

Feb 04, 2020

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jul 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1035*) in the SMC1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMC1A are known to be pathogenic (PMID: 26386245, 27334371, 28166369, 28548707, 31334757). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMC1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 532569). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Apr 20, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3103C>T (p.R1035*) alteration, located in exon 20 (coding exon 20) of the SMC1A gene, consists of a C to T substitution at nucleotide position 3103. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1035. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay._x000D_ _x000D_ Based on the available evidence, the SMC1A c.3103C>T (p.R1035*) alteration is classified as pathogenic for SMC1A-related developmental and epileptic encephalopathy; however, the clinical significance for Cornelia de Lange syndrome is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.91
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1556886124; hg19: chrX-53410045;