rs587784403

Variant names:

• chrX-53411822-C-T
• rs587784403
• NM_006306.4:c.1193G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_006306.4(SMC1A):​c.1193G>A​(p.Arg398Gln) variant causes a missense change involving the alteration of a 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.52
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy, 85, with or without midline brain defects

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cornelia de Lange syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant X-53411822-C-T is Pathogenic according to our data. Variant chrX-53411822-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 159938.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.1193G>A	p.Arg398Gln	missense_variant	Exon 7 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.1127G>A	p.Arg376Gln	missense_variant	Exon 8 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.1193G>A	p.Arg398Gln	missense_variant	Exon 7 of 25	1	NM_006306.4	ENSP00000323421.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22140011, 19842212, 28548707, 26358754, 24124034, 19701948) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	2.0	M;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.3	N;.
REVEL	Pathogenic	0.76
Sift	Benign	0.27	T;.
Sift4G	Benign	0.36	T;T
Polyphen		0.98	D;.
Vest4		0.60
MutPred		0.82		Loss of MoRF binding (P = 0.0471);.;
MVP		0.98
MPC		3.0
ClinPred		0.96	D
GERP RS		4.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.59
gMVP		0.75
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587784403; hg19: chrX-53438772; COSMIC: COSV100447086; COSMIC: COSV100447086;