rs200302125
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP3BP4_StrongBS1_SupportingBS2
The NM_000091.5(COL4A3):c.4421T>C(p.Leu1474Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,614,166 control chromosomes in the GnomAD database, including 23 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 0.0024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0046 ( 23 hom. )
Consequence
COL4A3
NM_000091.5 missense
NM_000091.5 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 7.67
Genes affected
COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM1
?
In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A3_HUMAN there are 39 pathogenic changes around while only 9 benign (81%) in NM_000091.5
PP3
?
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.038383782).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0046 (6724/1461862) while in subpopulation NFE AF= 0.00577 (6415/1111988). AF 95% confidence interval is 0.00565. There are 23 homozygotes in gnomad4_exome. There are 3231 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High Homozygotes in GnomAdExome4 at 23 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.4421T>C | p.Leu1474Pro | missense_variant | 48/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.48-2223A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.4421T>C | p.Leu1474Pro | missense_variant | 48/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.48-2223A>G | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00244 AC: 372AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00270 AC: 673AN: 249412Hom.: 0 AF XY: 0.00259 AC XY: 350AN XY: 135304
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GnomAD4 exome AF: 0.00460 AC: 6724AN: 1461862Hom.: 23 Cov.: 32 AF XY: 0.00444 AC XY: 3231AN XY: 727232
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GnomAD4 genome ? AF: 0.00244 AC: 372AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.00215 AC XY: 160AN XY: 74478
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:13Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5Benign:4
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2023 | Reported previously in association with COL4A3-related disorders and also reported as a polymorphism (PMID: 24130771, 25307543, 26346198, 12028435, 14871398); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30819905, 14871398, 17216251, 31865346, 26809805, 24130771, 12028435, 7987301, 29924831, 9269635, 11044206, 31027891, 11961012, 14582039, 27932480, 21897443, 30406062, 25229338, 29271581, 28658201, 31903434, 33391746, 31256874, 26346198, 25307543, 30295827, 29204651, 31477057, 32887937, 34426522, 33040356, 32939031, 34013111, 33654185, 35602506, 35260866, 36134775, 11134255, 36100708, 35090027, 37163122, Venda2023[Abstract], 37895316, 37915894) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 27, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | COL4A3: PM3:Strong, PM2:Supporting - |
Autosomal recessive Alport syndrome Pathogenic:2Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins-Biomnis | Nov 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 14, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 27, 2019 | A heterozygous missense variant was identified, NM_000091.4(COL4A3):c.4421T>C in exon 48 of 52 of the COL4A3 gene. This substitution is predicted to create a moderate amino acid change from leucine to proline at position 1474 of the protein, NP_000082.2(COL4A3):p.(Leu1474Pro). The leucine at this position has very high conservation (100 vertebrates, UCSC), and is located within the C4 functional domain. In silico software predicts this variant to be pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.27% (748 heterozygotes; 0 homozygotes). Previous reports of the pathogenicity of this variant are conflicting (ClinVar, Ottlewski, I. et al. (2019), Schapiro, D. et al. (2019)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). NB: This variant has been reclassified to a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) due to the reanalysis of published literature. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Sep 18, 2023 | PS3_Moderate, PM3_Strong, PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Apr 20, 2020 | - - |
Autosomal dominant Alport syndrome Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Jun 14, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 10, 2023 | Criteria applied: PP3 - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | May 01, 2024 | Pathogenic by Deafness Variation Database and by ClinVar based on PMID: 31477057. - |
COL4A3-related disorder Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 16, 2023 | The COL4A3 c.4421T>C variant is predicted to result in the amino acid substitution p.Leu1474Pro. In the compound heterozygous state with another pathogenic COL4A3 variant, the c.4421T>C (p.Leu1474Pro) variant has been reported in patients with autosomal recessive Alport syndrome or early progression to end-stage renal disease (Chatterjee et al. 2013. PubMed ID: 24130771; Gast et al. 2015. PubMed ID: 26346198; Nabais Sá et al. 2015. PubMed ID: 25307543; Boeckhaus et al. 2020. PubMed ID: 33040356). Of note, in the Chatterjee et al. study, the p.Leu1474Pro variant in the heterozygous state was also found in an unaffected brother and his son with unknown disease status. This variant in the heterozygous state has been repeatedly reported in patients with focal segmental glomerulosclerosis (Feltran et al. 2017. PubMed ID: 28658201; Gast et al. 2015. PubMed ID: 26346198; Malone et al. 2014. PubMed ID: 25229338). This variant was also reported in one patient with cervical artery dissection (Traenka et al. 2019. PubMed ID: 31903434). Furthermore, this variant along with a rare COL4A4 variant was reported in an identical twin brother-pair with cervical artery dissection (Brandt et al. 2018. PubMed ID: 29271581). This variant was reported in two siblings with IgA Nephropathy as variant of uncertain significance (Stapleton et al. 2020. PubMed ID: 31865346). However, the minor allele frequency of this variant in the general population reaches ~0.5%, which could be too high to be a primary cause of autosomal dominant COL4A3-related disease. Of note, incomplete penetrance has been reported in COL4A3-related disorders (Pescucci et al. 2004. PubMed ID: 15086897). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 17, 2018 | The COL4A3 c.4421T>C (p.Leu1474Pro) variant has been reported in at least five studies and is found in a total of nine probands, including five probands with clinical symptoms of Alport syndrome, two of which are siblings, in a compound heterozygous state and four proband in a heterozygous state, including one sibling pair (Chatterjee et al. 2013; Nabais Sa et al. 2015; Gast et al. 2016; Bierzynska et al. 2017; Brandt et al. 2018). This included two compound heterozygous probands with end stage renal disease (Nabais Sa et al. 2015). The remaining three compound heterozygous probands were identified to have variants in additional genes known to be associated with glomerulopathy (Chatterjee et al. 2013; Gast et al. 2016). The c.4421T>C (p.Leu1474Pro) variant was also observed in a presumed heterozygous state in the unaffected brother of a compound heterozygote and this brother's son (Chatterjee et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.004899 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Leu1474Pro variant is classified as likely pathogenic for COL4A3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Alport syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Dec 11, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 12, 2020 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 15, 2020 | The p.Leu1474Pro variant in COL4A3 is classified as benign because it has been identified in 0.5% (627/128566) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2022 | Variant summary: COL4A3 c.4421T>C (p.Leu1474Pro) results in a non-conservative amino acid change located in the non-collagenous domain (IPR001442) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 249412 control chromosomes, predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.6-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive phenotype (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.4421T>C, has been reported in the literature in several individuals affected with Alport Syndrome, focal segmental glomerulosclerosis (FSGS), steroid-resistant nephrotic syndrome (SRNS) and other nephrotic phenotypes, however without strong evidence for causality (e.g. Lemmink_1994, VanDerLoop_2000, Heidet_2001, Vega_2003, Chatterjee_2013, Malone_2014, Gast_2016, Weber_2016, Bierzynska_2017, Lata_2018), several of these reports described the variant as polymorphism, and in some of the reported cases atypical findings for Alport Syndrome were noted, or co-occurring variants in COL4A3 (with dominant mode of inheritance) or other genes could potentially explain the phenotype. These reports do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eighteen submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant with conflicting assessments, as pathogenic (n=1) / likely pathogenic (n=3), VUS (n=8), likely benign (n=4) / benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hearing impairment Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PS1_Strong, PM2_Moderate, PP3_Supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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