2-188996178-C-T
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7
The NM_000090.4(COL3A1):c.1662C>T(p.Pro554Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,612,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P554P) has been classified as Likely benign.
Frequency
Consequence
NM_000090.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
Publications
- autosomal dominant Ehlers-Danlos syndrome, vascular typeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
- Ehlers-Danlos syndrome, vascular typeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- polymicrogyria with or without vascular-type Ehlers-Danlos syndromeInheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.1662C>T | p.Pro554Pro | splice_region_variant, synonymous_variant | Exon 23 of 51 | 1 | NM_000090.4 | ENSP00000304408.4 | ||
COL3A1 | ENST00000450867.2 | c.1563C>T | p.Pro521Pro | splice_region_variant, synonymous_variant | Exon 22 of 50 | 1 | ENSP00000415346.2 | |||
COL3A1 | ENST00000713744.1 | c.1662C>T | p.Pro554Pro | splice_region_variant, synonymous_variant | Exon 23 of 49 | ENSP00000519048.1 | ||||
COL3A1 | ENST00000713745.1 | c.1608+388C>T | intron_variant | Intron 22 of 48 | ENSP00000519049.1 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151488Hom.: 0 Cov.: 30 show subpopulations
GnomAD2 exomes AF: 0.0000318 AC: 8AN: 251228 AF XY: 0.0000368 show subpopulations
GnomAD4 exome AF: 0.000107 AC: 156AN: 1461244Hom.: 0 Cov.: 31 AF XY: 0.0000990 AC XY: 72AN XY: 726960 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000264 AC: 4AN: 151488Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 73966 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Uncertain:2
This synonymous variant does not change the amino acid sequence of the COL3A1 protein. However, computational splicing tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This sequence change affects codon 554 of the COL3A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL3A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs373963384, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 459767). 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. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
This synonymous variant does not change the amino acid sequence of the COL3A1 protein. However, computational splicing tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at