6-116120105-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000493.4(COL10A1):c.2011T>C(p.Ser671Pro) variant causes a missense change involving the alteration of a non-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 (★★).
Frequency
Consequence
NM_000493.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL10A1 | ENST00000651968.1 | c.2011T>C | p.Ser671Pro | missense_variant | Exon 3 of 3 | NM_000493.4 | ENSP00000498802.1 | |||
NT5DC1 | ENST00000319550.9 | c.529+2160A>G | intron_variant | Intron 6 of 11 | 1 | NM_152729.3 | ENSP00000326858.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Metaphyseal chondrodysplasia, Schmid type Pathogenic:2
This COL10A1 variant has been previously identified in affected mother and her two affected sons as well as multiple affected individuals in another large family. c.2011T>C is located in the second noncollagenous domain (NC2), a region important to tertiary collagen structure in which many other diseaseâ€associated variants have been identified. This variant is absent from large population datasets and is listed in ClinVar as pathogenic by a single submitter (OMIM). Of three bioinformatics tools queried, two predict that the substitution would be possibly damaging, while one predicts that it would be tolerated. Additionally, the serine residue at this position is evolutionarily conserved across most higher order species assessed. This variant is likely pathogenic in this patient. -
- -
not provided Pathogenic:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29234170, 8986632) -
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 17477). This missense change has been observed in individuals with Schmid metaphyseal chondrodysplasia (PMID: 8986632, 29234170). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 671 of the COL10A1 protein (p.Ser671Pro). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at