rs545973022
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2
The NM_000093.5(COL5A1):c.3991G>A(p.Asp1331Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000516 in 1,551,102 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00032 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
COL5A1
NM_000093.5 missense
NM_000093.5 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 9.83
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 Benign. Variant got -7 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A1. . Gene score misZ 2.0682 (greater than the threshold 3.09). Trascript score misZ 4.1823 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 1, arterial disorder, Ehlers-Danlos syndrome, classic type.
BP4
Computational evidence support a benign effect (MetaRNN=0.035806328).
BS2
High AC in GnomAd4 at 49 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.3991G>A | p.Asp1331Asn | missense_variant | 50/66 | ENST00000371817.8 | |
COL5A1 | NM_001278074.1 | c.3991G>A | p.Asp1331Asn | missense_variant | 50/66 | ||
COL5A1 | XM_017014266.3 | c.3991G>A | p.Asp1331Asn | missense_variant | 50/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.3991G>A | p.Asp1331Asn | missense_variant | 50/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.3991G>A | p.Asp1331Asn | missense_variant | 50/66 | 2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000322 AC: 49AN: 152226Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.0000385 AC: 6AN: 156032Hom.: 0 AF XY: 0.0000122 AC XY: 1AN XY: 82126
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GnomAD4 exome AF: 0.0000222 AC: 31AN: 1398758Hom.: 0 Cov.: 31 AF XY: 0.0000130 AC XY: 9AN XY: 689892
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GnomAD4 genome AF: 0.000322 AC: 49AN: 152344Hom.: 1 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74494
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, classic type Pathogenic:1Other:1
Likely pathogenic, flagged submission | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 04-19-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2023 | 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 position is not a common mechanism of disease (Symoens et al., 2012; HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 27, 2023 | BS1 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MutPred
Loss of ubiquitination at K1335 (P = 0.1557);Loss of ubiquitination at K1335 (P = 0.1557);
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