rs914878176
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000091.5(COL4A3):āc.3472G>Cā(p.Gly1158Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,356 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). Synonymous variant affecting the same amino acid position (i.e. G1158G) has been classified as Likely benign.
Frequency
Consequence
NM_000091.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.3472G>C | p.Gly1158Arg | missense_variant | 40/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.243+10443C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.3472G>C | p.Gly1158Arg | missense_variant | 40/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.243+10443C>G | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000660 AC: 1AN: 151616Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249490Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135374
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461740Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 727166
GnomAD4 genome ? AF: 0.00000660 AC: 1AN: 151616Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74024
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2022 | Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene, where the majority of pathogenic missense variants occur; Not observed at significant frequency in large population cohorts (gnomAD); 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: 31589614, 34400539, 24052634) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1158 of the COL4A3 protein (p.Gly1158Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant and recessive COL4A3-related conditions (PMID: 24052634; Invitae). ClinVar contains an entry for this variant (Variation ID: 556767). 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) performed at Invitae indicates that this missense variant is expected to disrupt COL4A3 protein function. 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. - |
Autosomal recessive Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 23, 2018 | - - |
Alport syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Oct 04, 2017 | This individual is heterozygous for the c.3472G>C variant in the COL4A3 gene. This variant results in substitution of one of the invariant glycine residues, p.(Gly1158Arg), within the triple helical domain of the alpha 3 chain of type IV collagen. This variant has been previously described in individuals with autosomal recessive Alport syndrome by Storey et al J Am Soc Nephrol 2013 24: 1945-1954. This variant is considered to be likely pathogenic according to the ACMG guidelines. - |
Autosomal dominant Alport syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 19, 2020 | This COL4A3 variant has been reported in multiple individuals with clinically suspected autosomal recessive Alport syndrome and a second variant in this gene. COL4A3 c.3472G>C (rs914878176) is rare (<0.1%) in a large population dataset (gnomAD: 1/249490 total alleles; 0.0004%; no homozygotes), and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the glycine residue at this position is highly evolutionarily conserved across all species assessed. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.3472G>C to be uncertain at this time - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at