rs387906702
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_006306.4(SMC1A):c.2351T>C(p.Ile784Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I784V) has been classified as Uncertain significance.
Frequency
Consequence
NM_006306.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC1A | NM_006306.4 | c.2351T>C | p.Ile784Thr | missense_variant | 15/25 | ENST00000322213.9 | |
SMC1A | NM_001281463.1 | c.2285T>C | p.Ile762Thr | missense_variant | 16/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC1A | ENST00000322213.9 | c.2351T>C | p.Ile784Thr | missense_variant | 15/25 | 1 | NM_006306.4 | P1 | |
SMC1A | ENST00000375340.10 | c.2285T>C | p.Ile762Thr | missense_variant | 16/26 | 1 | |||
SMC1A | ENST00000675504.1 | c.2285T>C | p.Ile762Thr | missense_variant | 15/25 | ||||
SMC1A | ENST00000674590.1 | c.1583T>C | p.Ile528Thr | missense_variant | 13/23 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Congenital muscular hypertrophy-cerebral syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2010 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Center for Human Genetics, University of Leuven | Jan 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.52). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029929). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 20635401, 24124034, 24756084). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2020 | Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20635401, 24756084, 27159028, 24124034) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at