rs1057518666
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001854.4(COL11A1):c.2754+5G>A variant causes a splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 33)
Consequence
COL11A1
NM_001854.4 splice_donor_5th_base, intron
NM_001854.4 splice_donor_5th_base, intron
Scores
1
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 7.17
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 12 ACMG points.
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 1-102978703-C-T is Pathogenic according to our data. Variant chr1-102978703-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 374386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-102978703-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL11A1 | NM_001854.4 | c.2754+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000370096.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL11A1 | ENST00000370096.9 | c.2754+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_001854.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2017 | The c.2754+5G>A variant in the COL11A1 gene, using alternate nomenclature c.2755+5G>A, has been reported previously in the heterozygous state in association with Stickler syndrome (Richards et al., 2010). This variant destroys the splice donor site at intron 35, and is expected to cause abnormal gene splicing. The c.2754+5G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2754+5G>A as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change falls in intron 35 of the COL11A1 gene. It does not directly change the encoded amino acid sequence of the COL11A1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of autosomal dominant Stickler syndrome (PMID: 20513134; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2755+5G>A. ClinVar contains an entry for this variant (Variation ID: 374386). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Stickler syndrome type 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | May 01, 2016 | Our laboratory reported two molecular diagnoses in COL11A1 (NM_080630.2:c.2754+5G>A) and KRIT1 (NM_194456.1:c.146_147del) in an individual with hearing loss, tics, dysmorphic features, macrocephaly, vision loss, chronic otitis media, reactive airway disease, food allergy, urticaria, eczema, and keratosis pilaris. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
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: 13
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at