rs748026887
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000091.5(COL4A3):c.4347_4353del(p.Arg1450ValfsTer77) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
COL4A3
NM_000091.5 frameshift
NM_000091.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.60
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-227307800-TCACCCGA-T is Pathogenic according to our data. Variant chr2-227307800-TCACCCGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 550302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227307800-TCACCCGA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.4347_4353del | p.Arg1450ValfsTer77 | frameshift_variant | 48/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.48-2152_48-2146del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.4347_4353del | p.Arg1450ValfsTer77 | frameshift_variant | 48/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.48-2152_48-2146del | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249534Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135378
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461864Hom.: 0 AF XY: 0.0000220 AC XY: 16AN XY: 727238
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive Alport syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 05, 2019 | Variant summary: COL4A3 c.4347_4353delCCGACAC (p.Arg1450ValfsX77) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 249534 control chromosomes. c.4347_4353delCCGACAC has been reported in the literature in individuals affected with autosomal recessive Alport Syndrome (Ding_1995, Storey_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift variant c.4347_4353del (p.Arg1450ValfsTer77) in COL4A3 gene has been observed in individuals affected with Alport syndrome (Storey H et.al.,2013). This variant has been reported to the ClinVar database as Pathogenic .The p.Arg1450ValfsTer77 variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.002004% is reported in gnomAD. This variant causes a frameshift starting with codon Arginine 1450, changes this amino acid to Valine residue, and creates a premature Stop codon at position 77 of the new reading frame, denoted p.Arg1450ValfsTer77. For these reasons, this variant has been classified as Pathogenic . - |
Alport syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 06, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change creates a premature translational stop signal (p.Arg1450Valfs*77) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). This variant is present in population databases (rs748026887, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 7780062, 24052634). ClinVar contains an entry for this variant (Variation ID: 550302). For these reasons, this variant has been classified as Pathogenic. - |
Benign familial hematuria;C4746547:Autosomal dominant Alport syndrome;C4746745:Autosomal recessive Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 29, 2022 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at