rs104886363
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_033380.3(COL4A5):c.2732G>A(p.Gly911Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,098 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_033380.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.2732G>A | p.Gly911Glu | missense_variant | 32/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.2732G>A | p.Gly911Glu | missense_variant | 32/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000483338.1 | c.1556G>A | p.Gly519Glu | missense_variant | 16/20 | 1 | |||
COL4A5 | ENST00000361603.7 | c.2732G>A | p.Gly911Glu | missense_variant | 32/51 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome AF: 9.12e-7 AC: 1AN: 1096098Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 361558
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
COL4A5-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 26, 2023 | The COL4A5 c.2732G>A variant is predicted to result in the amino acid substitution p.Gly911Glu. This variant was reported in an individual with Alport syndrome and was reported to occur de novo in a female patient with features of a COL4A5-related disorder (Cheong et al. 2000. PubMed ID: 10684360; Yokota et al. 2016. PubMed ID: 27796712). At PreventionGenetics, we have observed the c.2732G>A variant in an individual with kidney disease (internal data). The p.Gly911Glu variant affects a Gly residue of the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
X-linked Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with COL4A5 -related disorder (PMID: 10684360). A different missense change at the same codon (p.Gly911Arg) has been reported to be associated with COL4A5 -related disorder (PMID: 29204651). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at