rs727503773

Variant names:

• chrX-53412949-CCTT-C
• rs727503773
• NM_006306.4:c.802_804delAAG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP3

The NM_006306.4(SMC1A):​c.802_804delAAG​(p.Lys268del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMC1A NM_006306.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.67
• Publications: 8 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53412949-CCTT-C is Pathogenic according to our data. Variant chrX-53412949-CCTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 180197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_006306.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006306.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	NM_006306.4	MANE Select	c.802_804delAAG	p.Lys268del	conservative_inframe_deletion	Exon 5 of 25	NP_006297.2
	SMC1A	NM_001281463.1		c.736_738delAAG	p.Lys246del	conservative_inframe_deletion	Exon 6 of 26	NP_001268392.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	ENST00000322213.9	TSL:1 MANE Select	c.802_804delAAG	p.Lys268del	conservative_inframe_deletion	Exon 5 of 25	ENSP00000323421.3
	SMC1A	ENST00000375340.10	TSL:1	c.736_738delAAG	p.Lys246del	conservative_inframe_deletion	Exon 6 of 26	ENSP00000364489.7
	SMC1A	ENST00000675504.1		c.736_738delAAG	p.Lys246del	conservative_inframe_deletion	Exon 5 of 25	ENSP00000502524.1

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Congenital muscular hypertrophy-cerebral syndrome (5)
1	-	-	Hirsutism;C0026826:Hypertonia;C0241654:Abnormal heart valve morphology;C0557874:Global developmental delay;C1843156:Progressive sensorineural hearing impairment;C4551563:Microcephaly (1)
1	-	-	SMC1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=46/54	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: rs727503773; hg19: chrX-53439899; COSMIC: COSV100446967;