rs587784416
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_006306.4(SMC1A):c.3146G>A(p.Arg1049Gln) variant causes a missense change. 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 (★★).
Frequency
Genomes: not found (cov: 21)
Consequence
SMC1A
NM_006306.4 missense
NM_006306.4 missense
Scores
8
8
1
Clinical Significance
Conservation
PhyloP100: 5.89
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 15 ACMG points.
PM1
In a coiled_coil_region (size 77) in uniprot entity SMC1A_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_006306.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMC1A. . Gene score misZ 6.4479 (greater than the threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, X-linked complex neurodevelopmental disorder, atypical Rett syndrome, Cornelia de Lange syndrome 2, developmental and epileptic encephalopathy, 85, with or without midline brain defects.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.924
PP5
Variant X-53382645-C-T is Pathogenic according to our data. Variant chrX-53382645-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53382645-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC1A | NM_006306.4 | c.3146G>A | p.Arg1049Gln | missense_variant | 21/25 | ENST00000322213.9 | |
SMC1A | NM_001281463.1 | c.3080G>A | p.Arg1027Gln | missense_variant | 22/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC1A | ENST00000322213.9 | c.3146G>A | p.Arg1049Gln | missense_variant | 21/25 | 1 | NM_006306.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD3 genomes
Cov.:
21
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 21
GnomAD4 genome
Cov.:
21
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital muscular hypertrophy-cerebral syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 11, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1049 of the SMC1A protein (p.Arg1049Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 19701948). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159954). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMC1A protein function. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 30, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2016 | The R1049Q variant in the SMC1A gene has been reported previously as a de novo change in an individual with Cornelia de Lange syndrome (Liu et al., 2009). The R1049Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1049Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. The R1049Q variant maps to the coiled-coil domain, which may interfere with heterodimer formation and disrupt the interaction with other cohesin subunits (Mannini et al., 2010). We interpret R1049Q as a pathogenic variant. - |
Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Lab, CHRU Brest | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of helix (P = 0.027);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at