rs1554726251
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000093.5(COL5A1):c.5165dup(p.Val1723CysfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
COL5A1
NM_000093.5 frameshift
NM_000093.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.15
Genes affected
COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-134834996-A-AC is Pathogenic according to our data. Variant chr9-134834996-A-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519656.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.5165dup | p.Val1723CysfsTer55 | frameshift_variant | 65/66 | ENST00000371817.8 | NP_000084.3 | |
LOC101448202 | NR_103451.2 | n.71-14788_71-14787insG | intron_variant, non_coding_transcript_variant | |||||
COL5A1 | NM_001278074.1 | c.5165dup | p.Val1723CysfsTer55 | frameshift_variant | 65/66 | NP_001265003.1 | ||
COL5A1 | XM_017014266.3 | downstream_gene_variant | XP_016869755.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.5165dup | p.Val1723CysfsTer55 | frameshift_variant | 65/66 | 1 | NM_000093.5 | ENSP00000360882 | P4 | |
COL5A1 | ENST00000371820.4 | c.5165dup | p.Val1723CysfsTer55 | frameshift_variant | 65/66 | 2 | ENSP00000360885 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
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
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2017 | The c.5165dupC variant, located in coding exon 65 of the COL5A1 gene, results from a duplication of C at nucleotide position 5165, causing a translational frameshift with a predicted alternate stop codon (p.V1723Cfs*55). The stop codon occurs at the 3' terminus of COL5A1 and is not expected to trigger nonsense-mediated mRNA decay. However, this alteration affect the significant portion of the C-terminal domain, which is generally known to be involved in Collagen trimer formation and folding (Chessler SD et al. J. Biol. Chem., 1993 Aug;268:18218-25; Lees JF et al. J. Biol. Chem., 1994 Sep;269:24354-60; McIntosh I et al. Hum. Mutat., 1995;5:121-5). In addition, COL5A1 variants downstream of this alteration have been reported in individuals with classic Ehlers Danlos syndrome, further supporting the importance of the C-terminus impacted by this alteration (Mitchell AL et al. Hum. Mutat., 2009 Jun;30:995-1002; Symoens S et al. Hum. Mutat., 2012 Oct;33:1485-93). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
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