rs937550597
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000092.5(COL4A4):c.2590G>A(p.Gly864Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,904 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G864W) has been classified as Pathogenic.
Frequency
Consequence
NM_000092.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A4 | NM_000092.5 | c.2590G>A | p.Gly864Arg | missense_variant | 30/48 | ENST00000396625.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A4 | ENST00000396625.5 | c.2590G>A | p.Gly864Arg | missense_variant | 30/48 | 5 | NM_000092.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152070Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727226
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74280
ClinVar
Submissions by phenotype
Autosomal recessive Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 10, 2017 | - - |
Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 04, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 864 of the COL4A4 protein (p.Gly864Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with Alport syndrome (PMID: 16338941, 24052634). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 550588). 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 COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at