rs587784427
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP5_Moderate
The NM_005445.4(SMC3):c.2338G>C(p.Glu780Gln) variant causes a missense 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E780D) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
SMC3
NM_005445.4 missense
NM_005445.4 missense
Scores
5
8
6
Clinical Significance
Conservation
PhyloP100: 9.33
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a coiled_coil_region (size 247) in uniprot entity SMC3_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_005445.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, SMC3
PP5
?
Variant 10-110599723-G-C is Pathogenic according to our data. Variant chr10-110599723-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159976.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC3 | NM_005445.4 | c.2338G>C | p.Glu780Gln | missense_variant | 21/29 | ENST00000361804.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC3 | ENST00000361804.5 | c.2338G>C | p.Glu780Gln | missense_variant | 21/29 | 1 | NM_005445.4 | P1 |
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: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.2641);
MVP
MPC
ClinPred
D
GERP RS
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