rs576976549
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000093.5(COL5A1):c.2484+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,600,244 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000077 ( 0 hom. )
Consequence
COL5A1
NM_000093.5 splice_donor_region, intron
NM_000093.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00001650
2
Clinical Significance
Conservation
PhyloP100: 0.0540
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 Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 9-134782726-C-T is Benign according to our data. Variant chr9-134782726-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 385270.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
High AC in GnomAdExome4 at 111 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.2484+6C>T | splice_donor_region_variant, intron_variant | ENST00000371817.8 | |||
COL5A1 | NM_001278074.1 | c.2484+6C>T | splice_donor_region_variant, intron_variant | ||||
COL5A1 | XM_017014266.3 | c.2484+6C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.2484+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_000093.5 | P4 | |||
COL5A1 | ENST00000371820.4 | c.2484+6C>T | splice_donor_region_variant, intron_variant | 2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151442Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251154Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135854
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GnomAD4 exome AF: 0.0000766 AC: 111AN: 1448802Hom.: 0 Cov.: 33 AF XY: 0.0000791 AC XY: 57AN XY: 720796
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GnomAD4 genome AF: 0.0000264 AC: 4AN: 151442Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 73900
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | COL5A1: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2020 | - - |
Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change falls in intron 29 of the COL5A1 gene. It does not directly change the encoded amino acid sequence of the COL5A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs576976549, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 385270). 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 is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
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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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at