2-227266473-G-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5
The NM_000091.5(COL4A3):c.1372G>C(p.Gly458Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G458E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000091.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.1372G>C | p.Gly458Arg | missense_variant | 22/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.656-538C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.1372G>C | p.Gly458Arg | missense_variant | 22/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.656-538C>G | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249378Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135320
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727176
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2023 | Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 10, 2020 | The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. The frequency of this variant in the general population is consistent with pathogenicity. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly458 amino acid residue in COL4A3. Other variant(s) that disrupt this residue have been observed in individuals with COL4A3-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. ClinVar contains an entry for this variant (Variation ID: 447166). This missense change has been observed in individuals with clinical features of autosomal dominant Alport syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs757341933, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 458 of the COL4A3 protein (p.Gly458Arg). - |
Benign familial hematuria;C4746547:Autosomal dominant Alport syndrome;C4746745:Autosomal recessive Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at