rs767925708
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000093.5(COL5A1):c.2543G>A(p.Arg848His) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,280 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R848C) has been classified as Likely benign.
Frequency
Consequence
NM_000093.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.2543G>A | p.Arg848His | missense_variant | 30/66 | ENST00000371817.8 | |
COL5A1 | NM_001278074.1 | c.2543G>A | p.Arg848His | missense_variant | 30/66 | ||
COL5A1 | XM_017014266.3 | c.2543G>A | p.Arg848His | missense_variant | 30/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.2543G>A | p.Arg848His | missense_variant | 30/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.2543G>A | p.Arg848His | missense_variant | 30/66 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250078Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135618
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461108Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726842
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2017 | The p.R848H variant (also known as c.2543G>A), located in coding exon 30 of the COL5A1 gene, results from a G to A substitution at nucleotide position 2543. The arginine at codon 848 is replaced by histidine, an amino acid with highly 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 18, 2021 | The COL5A1 c.2543G>A; p.Arg848His variant (rs767925708), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 519654). The variant is reported in the non-Finnish European population with an allele frequency of 0.0036% (4/112,686 alleles) in the Genome Aggregation Database. The arginine at codon 848 is part of the highly conserved Gly-X-Y repeat region, the arginine is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.757). However, due to limited information, the clinical significance of the p.Arg848His variant is uncertain at this time. - |
Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 13, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL5A1 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 519654). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. This variant is present in population databases (rs767925708, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 848 of the COL5A1 protein (p.Arg848His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at