rs797045069
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006306.4(SMC1A):c.2547del(p.Ile849MetfsTer12) variant causes a frameshift 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Consequence
SMC1A
NM_006306.4 frameshift
NM_006306.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.479
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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-53399603-CT-C is Pathogenic according to our data. Variant chrX-53399603-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 209192.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC1A | NM_006306.4 | c.2547del | p.Ile849MetfsTer12 | frameshift_variant | 16/25 | ENST00000322213.9 | |
SMC1A | NM_001281463.1 | c.2481del | p.Ile827MetfsTer12 | frameshift_variant | 17/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC1A | ENST00000322213.9 | c.2547del | p.Ile849MetfsTer12 | frameshift_variant | 16/25 | 1 | NM_006306.4 | P1 | |
SMC1A | ENST00000375340.10 | c.2481del | p.Ile827MetfsTer12 | frameshift_variant | 17/26 | 1 | |||
SMC1A | ENST00000675504.1 | c.2481del | p.Ile827MetfsTer12 | frameshift_variant | 16/25 | ||||
SMC1A | ENST00000674590.1 | c.1779del | p.Ile593MetfsTer12 | frameshift_variant | 14/23 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital muscular hypertrophy-cerebral syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 17, 2013 | This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a 21-year-old female with intellectual disbility, autistic features, intractable seizures, wide-based gait, dysmorphisms, 2-3 toe syndactyly, short stature, microcephaly, hyperextensibility, osteopenia - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2018 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at