chr9-134812672-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_000093.5(COL5A1):c.3812C>T(p.Pro1271Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000301 in 1,593,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1271R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000093.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.3812C>T | p.Pro1271Leu | missense_variant | 48/66 | ENST00000371817.8 | |
COL5A1 | NM_001278074.1 | c.3812C>T | p.Pro1271Leu | missense_variant | 48/66 | ||
COL5A1 | XM_017014266.3 | c.3812C>T | p.Pro1271Leu | missense_variant | 48/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.3812C>T | p.Pro1271Leu | missense_variant | 48/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.3812C>T | p.Pro1271Leu | missense_variant | 48/66 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000284 AC: 6AN: 211100Hom.: 0 AF XY: 0.0000353 AC XY: 4AN XY: 113454
GnomAD4 exome AF: 0.0000319 AC: 46AN: 1441152Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 29AN XY: 714612
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 21, 2022 | The COL5A1 c.3812C>T; p.Pro1271Leu variant (rs771146636), to our knowledge, is not reported in the literature in an individual with Ehlers-Danlos syndrome, but is listed in the ClinVar database (Variation ID: 459682). This variant is found in the general population with an overall allele frequency of 0.0028% (6/211,100 alleles) in the Genome Aggregation Database. The proline at codon 1271 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.571). Due to limited information, the clinical significance of the p.Pro1271Leu variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 12, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2022 | Reported as a variant of uncertain significance in an individual with a platelet function disorder (Downes et al., 2019).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (Symoens et al., 2012; HGMD); This variant is associated with the following publications: (PMID: 31064749) - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2023 | The p.P1271L variant (also known as c.3812C>T), located in coding exon 48 of the COL5A1 gene, results from a C to T substitution at nucleotide position 3812. The proline at codon 1271 is replaced by leucine, an amino acid with similar properties. The alteration was reported in a cohort of subjects with bleeding disorders (Downes K et al. Blood, 2019 Dec;134:2082-2091). 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. - |
Abnormal bleeding Uncertain:1
Uncertain significance, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at