rs111840783
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_000090.4(COL3A1):c.3938A>G(p.Lys1313Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,614,080 control chromosomes in the GnomAD database, including 3 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 0.00078 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 3 hom. )
Consequence
COL3A1
NM_000090.4 missense
NM_000090.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 7.50
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 Benign. Variant got -9 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ: 4.0879 (greater than the threshold 3.09). Trascript score misZ: 4.5995 (greater than threshold 3.09). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. GenCC has associacion of the gene with Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.3177298).
BP6
Variant 2-189010292-A-G is Benign according to our data. Variant chr2-189010292-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161218.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=9, Benign=6}. Variant chr2-189010292-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000782 (119/152242) while in subpopulation NFE AF= 0.00138 (94/68044). AF 95% confidence interval is 0.00115. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COL3A1 | ENST00000304636.9 | c.3938A>G | p.Lys1313Arg | missense_variant | 49/51 | 1 | NM_000090.4 | ENSP00000304408.4 | ||
| COL3A1 | ENST00000450867.2 | c.3839A>G | p.Lys1280Arg | missense_variant | 48/50 | 1 | ENSP00000415346.2 | |||
| COL3A1 | ENST00000487010.1 | n.1035A>G | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes 0.000782 AC: 119AN: 152242Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000776 AC: 195AN: 251428Hom.: 0 AF XY: 0.000795 AC XY: 108AN XY: 135894
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GnomAD4 exome AF: 0.00158 AC: 2307AN: 1461838Hom.: 3 Cov.: 32 AF XY: 0.00155 AC XY: 1130AN XY: 727218
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GnomAD4 genome 0.000782 AC: 119AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38AN XY: 74394
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:15
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Uncertain:2Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 26, 2024 | - - |
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Aug 01, 2016 | Found in patient having exome sequencing for an unrelated indication. No known history of Ehlers-Danlos syndrome, type IV - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not specified Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 27, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 14, 2018 | Variant summary: COL3A1 c.3938A>G (p.Lys1313Arg) results in a conservative amino acid change located in the Fibrillar collagen, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 0.0008 in 277186 control chromosomes (gnomAD). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1067-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Ehlers-Danlos Syndrome, Vascular Type phenotype (1.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.3938A>G, has been reported in the literature in individuals affected with Ehlers-Danlos Syndrome, Vascular Type. A publication, Stembridge_2015, cites the variant to occur in a patient and sister that did not present with features of vascular EDS, along with finding collagen and biochemistry to be normal. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 2017 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in gnomAD at a MaxMAF of 0.016% (199/126780 European chrs - high for disease incidence of 1/200,000). It has been classified in ClinVar with 1 star as VUS by GeneDx and CSER_CC_NCGL and as Likely benign by Ambry. It is present in HGMD in 4 papers - comments suggest VUS. - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 23, 2024 | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:3
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 14, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 07, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 11, 2022 | This alteration is classified as likely 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. - |
not provided Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 19, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | COL3A1: BS2 - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 06, 2023 | - - |
Ehlers-Danlos syndrome Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 25, 2022 | - - |
| Benign, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Apr 01, 2018 | The COL3A1 variant designated as NM_000090.3:c.3938A>G (p.Lys1313Arg) is classified as likely benign. It is present in approximately 1/380 individuals of European non-Finnish ancestry (exac.broadinstitute.org). That is more common than any known aneurysm frequency, and as such, this variant can be excluded as a single cause for vascular Ehlers-Danlos syndrome. This high variant frequency may also explain reports of many previously tested individuals with vascular events who also have this variant. The crystal structure of the carboxyl-terminal propeptide of the proa1(III) chains encoded by COL3A1 has been well-defined. The COL3A1 p.Lys1313Arg variant is in the domain that directs chain-chain association. The residue is on an outward-facing region that does not participate in chain interaction and is predicted not to be involved in protein interaction (Stembridge et al, 2015 PMID:25846194). Wordsworth, Ogilvie, & Sykes (1991, PMID: 2049575) also looked at this region and found families in which the variant did not co-segregate with an aneurysm phenotype in the family, and the presence of the variant did not seem to exacerbate clinical symptoms. Stembridge et al (2015) described a family with the COL3A1 p. Lys1313Arg variant wherein the proband had a clinical appearance of Ehlers-Danlos syndrome, hypermobility type, and two relatives had a history of joint hypermobility. The association between the variant and the family’s phenotype of hypermobility was not defined. Patients with the COL3A1 p.Lys1313Arg variant who were tested at the UW Collagen Diagnostic Laboratory did not have clinical features that qualified them for a diagnosis of vascular Ehlers-Danlos syndrome, or had other variants associated with connective tissue disorders to account for their connective tissue phenotypes. The combined data provide weak evidence than the COL3A1 p.Lys1313Arg variant is likely benign in the context of vascular Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV). Several reports have described varying features in families with COL3A1 heterozygous missense variants (Leistritz et al., 2011, PMID:21637106, Cortini et al., 2017 PMID:28183226). Thus clinical associations other than those described in the literature cannot be excluded. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <0.1% probability of pathogenicity, which is consistent with a classification of benign. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. - |
Loeys-Dietz syndrome Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Aug 01, 2014 | - - |
Connective tissue disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Jan 05, 2022 | COL3A1 NM_000090.3 exon 49 p.Lys1313Arg (c.3938A>G): This variant has been reported in the literature in two individuals with vascular anomalies (Pickup 2011 PMID: 21086191, Traenka 2019 PMID:31903434). However, this variant is also present in 0.1% (91/64586) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-189010292-A-G?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:161218). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
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
L;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N
REVEL
Uncertain
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
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