rs886041239
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP2PP5_Very_StrongBP4
The NM_005445.4(SMC3):c.1942A>G(p.Met648Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
SMC3
NM_005445.4 missense
NM_005445.4 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 7.10
Genes affected
SMC3 (HGNC:2468): (structural maintenance of chromosomes 3) This gene belongs to the SMC3 subfamily of SMC proteins. The encoded protein occurs in certain cell types as either an intracellular, nuclear protein or a secreted protein. The nuclear form, known as structural maintenance of chromosomes 3, is a component of the multimeric cohesin complex that holds together sister chromatids during mitosis, enabling proper chromosome segregation. Post-translational modification of the encoded protein by the addition of chondroitin sulfate chains gives rise to the secreted proteoglycan bamacan, an abundant basement membrane protein. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, SMC3
PP5
?
Variant 10-110593202-A-G is Pathogenic according to our data. Variant chr10-110593202-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3904004). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC3 | NM_005445.4 | c.1942A>G | p.Met648Val | missense_variant | 18/29 | ENST00000361804.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC3 | ENST00000361804.5 | c.1942A>G | p.Met648Val | missense_variant | 18/29 | 1 | NM_005445.4 | P1 | |
SMC3 | ENST00000684988.1 | n.2587A>G | non_coding_transcript_exon_variant | 16/25 | |||||
SMC3 | ENST00000692792.1 | n.2061A>G | non_coding_transcript_exon_variant | 18/19 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279893, PMID:26633542). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26633542). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 648 of the SMC3 protein (p.Met648Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SMC3-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 279893). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMC3 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2016 | The M648V pathogenic variant in the SMC3 gene has been reported previously as a somatic variant in a head and neck squamous cell carcinoma, but has not been reported in the germline (Stransky et al., 2011). The M648V variant was not observed in approximately 6,500 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 M648V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The M648V variant is located within the flexible hinge region of the protein, which is essential for protein function (Gruber et al., 2006). We interpret M648V as a pathogenic variant. - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Lab, Policlinico S. Orsola.Malpighi | Nov 09, 2018 | The Met648Val variant in SMC3 is extremely rare (never reported in GnomAD exomes and genomes) and missense variants of this gene are a known cause of disease. Furthermore, this variant is de novo in the patient and there is no family history of the disease. On the other hand, prediction scores are conflicting (MutationTaster: disease-causing; SIFT: tolerated) and the clinical picture of this patient is not reminiscent of Cornelia de Lange syndrome. We interpret Met648Val as a likely pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of catalytic residue at M648 (P = 0.0123);
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