chrX-53405254-CTCT-C

Position:

• chrX-53405254-CTCT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_006306.4(SMC1A):​c.2046_2048delAGA​(p.Glu683del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMC1A NM_006306.4 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.76

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a coiled_coil_region (size 275) in uniprot entity SMC1A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006306.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006306.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-53405254-CTCT-C is Pathogenic according to our data. Variant chrX-53405254-CTCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212266.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53405254-CTCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.2046_2048delAGA	p.Glu683del	disruptive_inframe_deletion	12/25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.1980_1982delAGA	p.Glu661del	disruptive_inframe_deletion	13/26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.2046_2048delAGA	p.Glu683del	disruptive_inframe_deletion	12/25	1	NM_006306.4	ENSP00000323421.3

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

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Computational scores

Source: dbNSFP v4.3

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: rs797045992; hg19: chrX-53432186;