rs140943202
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_000093.5(COL5A1):c.1295C>T(p.Pro432Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000589 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P432P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
COL5A1
NM_000093.5 missense
NM_000093.5 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 4.63
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 Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, COL5A1
BS2
?
High AC in GnomAd4 at 20 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.1295C>T | p.Pro432Leu | missense_variant | 8/66 | ENST00000371817.8 | |
COL5A1 | NM_001278074.1 | c.1295C>T | p.Pro432Leu | missense_variant | 8/66 | ||
COL5A1 | XM_017014266.3 | c.1295C>T | p.Pro432Leu | missense_variant | 8/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.1295C>T | p.Pro432Leu | missense_variant | 8/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.1295C>T | p.Pro432Leu | missense_variant | 8/66 | 2 | A2 | ||
COL5A1 | ENST00000469093.1 | n.34C>T | non_coding_transcript_exon_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152158Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000603 AC: 15AN: 248818Hom.: 0 AF XY: 0.0000520 AC XY: 7AN XY: 134722
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GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461770Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34AN XY: 727186
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GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74322
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 13, 2023 | BS1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; HGMD); This variant is associated with the following publications: (PMID: 22696272) - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 09, 2018 | The p.P432L variant (also known as c.1295C>T), located in coding exon 8 of the COL5A1 gene, results from a C to T substitution at nucleotide position 1295. The proline at codon 432 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Benign
Sift
Benign
D;.
Sift4G
Uncertain
D;D
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at