rs745472969
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000091.5(COL4A3):c.1459G>A(p.Gly487Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000929 in 1,613,808 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G487C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000091.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.1459G>A | p.Gly487Ser | missense_variant | 23/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.656-1108C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.1459G>A | p.Gly487Ser | missense_variant | 23/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.656-1108C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152054Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000108 AC: 27AN: 249514Hom.: 0 AF XY: 0.0000813 AC XY: 11AN XY: 135374
GnomAD4 exome AF: 0.0000971 AC: 142AN: 1461754Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62AN XY: 727186
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74246
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2022 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 487 of the COL4A3 protein (p.Gly487Ser). This variant is present in population databases (rs745472969, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with COL4A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1309543). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Autosomal dominant Alport syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense c.1459G>A(p.Gly487Ser) variant in COL4A3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.01% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Gly at position 487 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly487Ser in COL4A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at