rs760539229
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2
The NM_000093.5(COL5A1):c.2354C>T(p.Pro785Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,613,858 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).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
COL5A1
NM_000093.5 missense
NM_000093.5 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 4.39
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 Uncertain_significance. Variant got 0 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000093.5
PP2
?
Missense variant where missense usually causes diseases, COL5A1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.784
BS2
?
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.2354C>T | p.Pro785Leu | missense_variant | 27/66 | ENST00000371817.8 | |
LOC124902301 | XR_007061843.1 | n.1000G>A | non_coding_transcript_exon_variant | 1/2 | |||
COL5A1 | NM_001278074.1 | c.2354C>T | p.Pro785Leu | missense_variant | 27/66 | ||
COL5A1 | XM_017014266.3 | c.2354C>T | p.Pro785Leu | missense_variant | 27/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.2354C>T | p.Pro785Leu | missense_variant | 27/66 | 1 | NM_000093.5 | P4 | |
ENST00000666389.1 | n.791G>A | non_coding_transcript_exon_variant | 1/2 | ||||||
COL5A1 | ENST00000371820.4 | c.2354C>T | p.Pro785Leu | missense_variant | 27/66 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249538Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135162
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GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461524Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727006
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152334Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; 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/Y} position is not a common mechanism of disease (Symoens et al., 2012; Stenson et al., 2014) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | - - |
Ehlers-Danlos syndrome, classic type Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Nov 12, 2018 | COL5A1 NM_000093.4 exon 27 p.Pro785Leu (c.2354C>T): This variant has not been reported in the literature and is present in 0.009% (3/30444) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/9-137666727-C-T). This variant is present in ClinVar (Variation ID:212949). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | COL5A1 NM_000093.4 exon 27 p.Pro785Leu (c.2354C>T): This variant has not been reported in the literature and is present in 0.009% (3/30444) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/9-137666727-C-T). This variant is present in ClinVar (Variation ID:212949). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
T;T
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at P785 (P = 0.0351);Gain of catalytic residue at P785 (P = 0.0351);
MVP
MPC
ClinPred
D
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