rs1248348633
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2
The NM_000090.4(COL3A1):c.1129G>A(p.Ala377Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,556,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
COL3A1
NM_000090.4 missense
NM_000090.4 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 1.53
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 3 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000090.4
PP2
?
Missense variant where missense usually causes diseases, COL3A1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.1129G>A | p.Ala377Thr | missense_variant | 16/51 | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.1129G>A | p.Ala377Thr | missense_variant | 16/51 | 1 | NM_000090.4 | P1 | |
COL3A1 | ENST00000450867.2 | c.1050+499G>A | intron_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151958Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000305 AC: 5AN: 164040Hom.: 0 AF XY: 0.0000232 AC XY: 2AN XY: 86068
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GnomAD4 exome AF: 0.0000121 AC: 17AN: 1404582Hom.: 0 Cov.: 31 AF XY: 0.0000130 AC XY: 9AN XY: 693196
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces alanine with threonine at codon 377 of the COL3A1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with vascular anomaly (PMID: 28655553). This variant has also been identified in 6/195374 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 377 of the COL3A1 protein (p.Ala377Thr). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with vascular anomalies (PMID: 28655553). ClinVar contains an entry for this variant (Variation ID: 529323). 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. 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:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 15, 2023 | This missense variant replaces alanine with threonine at codon 377 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with vascular anomalies (PMID: 28655553). This variant has been identified in 6/195374 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. - |
COL3A1-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 22, 2023 | The COL3A1 c.1129G>A variant is predicted to result in the amino acid substitution p.Ala377Thr. This variant was reported in the heterozygous state in an individual with vascular anomalies (Supplementary Table II, Patient ID R837, Mattassi et al. 2018. PubMed ID: 28655553). This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-189858165-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MutPred
Gain of phosphorylation at A377 (P = 0.0113);Gain of phosphorylation at A377 (P = 0.0113);
MVP
MPC
ClinPred
T
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