rs1131691328
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_000090.4(COL3A1):c.877A>G(p.Asn293Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. N293K) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
COL3A1
NM_000090.4 missense
NM_000090.4 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 5.96
Genes affected
COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000090.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, COL3A1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.39136732).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.877A>G | p.Asn293Asp | missense_variant | 12/51 | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.877A>G | p.Asn293Asp | missense_variant | 12/51 | 1 | NM_000090.4 | P1 | |
COL3A1 | ENST00000450867.2 | c.877A>G | p.Asn293Asp | missense_variant | 12/50 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2017 | A variant of uncertain significance has been identified in the COL3A1 gene. The N293D variant has not been published as pathogenic or been reported as benign to our knowledge. Thid variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N293D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, while the N293D variant is located in the triple helical region of the COL3A1 gene, it does not affect a Glycine residue in a Gly-X-Y motif, as the majority of pathogenic missense variants do (Stenson et al., 2014; Symoens et al., 2012). - |
Ehlers-Danlos syndrome, type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 03, 2022 | 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) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 429338). This missense change has been observed in individual(s) with clinical features of COL3A1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 293 of the COL3A1 protein (p.Asn293Asp). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at N293 (P = 0.3898);Gain of catalytic residue at N293 (P = 0.3898);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at