rs398122828
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_001854.4(COL11A1):c.3816+1G>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
COL11A1
NM_001854.4 splice_donor
NM_001854.4 splice_donor
Scores
5
1
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 7.30
Genes affected
COL11A1 (HGNC:2186): (collagen type XI alpha 1 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Mutations in this gene are associated with type II Stickler syndrome and with Marshall syndrome. A single-nucleotide polymorphism in this gene is also associated with susceptibility to lumbar disc herniation. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.009776794 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of -8, new splice context is: cagGTgtag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-102915630-C-G is Pathogenic according to our data. Variant chr1-102915630-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 976188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-102915630-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL11A1 | NM_001854.4 | c.3816+1G>C | splice_donor_variant | ENST00000370096.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL11A1 | ENST00000370096.9 | c.3816+1G>C | splice_donor_variant | 1 | NM_001854.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 14, 2023 | Identified in multiple unrelated patients with Marshall syndrome in the published literature (Annunen et al., 1999; Khalifa et al., 2014); Damages or destroys the splice donor site in intron 50, and is expected to cause abnormal gene splicing; if the splice outcome is exon skip, the loss of the encoded residues in the triple helical region is expected to disrupt normal protein folding and function (Stenson et al., 2014; Acke et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS50+1G>C; This variant is associated with the following publications: (PMID: 25525159, 25073711, 10486316, 25240749) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 29, 2023 | Studies have shown that disruption of this splice site results in skipping of exon 51, but is expected to preserve the integrity of the reading-frame (PMID: 9529347). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 976188). Disruption of this splice site has been observed in individual(s) with autosomal dominant Marshall or Stickler syndrome (PMID: 9529347, 19449424, 25240749). In at least one individual the variant was observed to be de novo. 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 affects a donor splice site in intron 50 of the COL11A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. - |
Marshall syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 19, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 9
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at