chr2-227295295-A-AGAG
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_000091.5(COL4A3):c.3546_3548dup(p.Gly1183_Asn1183insGly) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
COL4A3
NM_000091.5 inframe_insertion
NM_000091.5 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.388
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000091.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 2-227295295-A-AGAG is Pathogenic according to our data. Variant chr2-227295295-A-AGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438655.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.3546_3548dup | p.Gly1183_Asn1183insGly | inframe_insertion | 41/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.243+10164_243+10165insCTC | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.3546_3548dup | p.Gly1183_Asn1183insGly | inframe_insertion | 41/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.243+10164_243+10165insCTC | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727222
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2021 | Not observed in large population cohorts (Lek et al., 2016); In-frame insertion of 1 amino acid in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This variant, c.3546_3548dup, results in the insertion of 1 amino acid(s) of the COL4A3 protein (p.Gly1183dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Alport syndrome (PMID: 30586318; Invitae). ClinVar contains an entry for this variant (Variation ID: 438655). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | COL4A3: PM1, PM2, PM4:Supporting, PS4:Supporting - |
Autosomal dominant Alport syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Oct 31, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 11, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM4. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jul 28, 2022 | - - |
COL4A3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | The COL4A3 c.3546_3548dupAGG variant is predicted to result in an in-frame duplication (p.Gly1183dup). This variant has been reported in the heterozygous state in an individual with glomerulopathy (Table S7, Groopman et al. 2019. PubMed ID: 30586318). In addition, at PreventionGenetics, we have previously found this variant in the heterozygous state in an individual tested for the nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) panel. This one amino acid duplication variant occurs at the conserved triple helical domain (residues 43-1438) of the COL4A3 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). The consequence of this glycine duplication variant is expected to disturb the conserved triple helical Gly-X-Y repeats; and the same type of one amino acid duplication/insertion variant at a different but nearby location has been reported in an individual with isolated hematuria (c.3547_3548insGGA resulting in p.Gly1183_Asn1184insArg at Slajpah et al. 2007. PubMed ID: 17396119). The p.Gly1183dup variant is interpreted as likely pathogenic. - |
Proteinuria;C0239937:Microscopic hematuria;C1654921:Moderate albuminuria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Macroscopic hematuria Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Alport syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 03, 2020 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at