rs75817442
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_005445.4(SMC3):āc.1680T>Cā(p.Tyr560=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000684 in 1,612,864 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0037 ( 4 hom., cov: 33)
Exomes š: 0.00037 ( 4 hom. )
Consequence
SMC3
NM_005445.4 synonymous
NM_005445.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.44
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 Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
?
Variant 10-110591000-T-C is Benign according to our data. Variant chr10-110591000-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159969.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}.
BP7
?
Synonymous conserved (PhyloP=2.44 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00366 (557/152312) while in subpopulation AFR AF= 0.0131 (546/41568). AF 95% confidence interval is 0.0122. There are 4 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 557 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC3 | NM_005445.4 | c.1680T>C | p.Tyr560= | synonymous_variant | 17/29 | ENST00000361804.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC3 | ENST00000361804.5 | c.1680T>C | p.Tyr560= | synonymous_variant | 17/29 | 1 | NM_005445.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00366 AC: 557AN: 152194Hom.: 4 Cov.: 33
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GnomAD3 exomes AF: 0.000995 AC: 250AN: 251364Hom.: 1 AF XY: 0.000729 AC XY: 99AN XY: 135858
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GnomAD4 exome AF: 0.000375 AC: 547AN: 1460552Hom.: 4 Cov.: 30 AF XY: 0.000337 AC XY: 245AN XY: 726634
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GnomAD4 genome ? AF: 0.00366 AC: 557AN: 152312Hom.: 4 Cov.: 33 AF XY: 0.00346 AC XY: 258AN XY: 74470
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 3 Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SMC3: BP4, BS1, BS2 - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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