NM_000092.5:c.1441G>A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000092.5(COL4A4):c.1441G>A(p.Gly481Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,568 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).
Frequency
Consequence
NM_000092.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151990Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000842 AC: 21AN: 249452Hom.: 0 AF XY: 0.0000813 AC XY: 11AN XY: 135336
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461460Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727064
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152108Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74352
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:3
- -
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 481 of the COL4A4 protein (p.Gly481Ser). This variant is present in population databases (rs181528936, gnomAD 0.06%). This missense change has been observed in individuals with clinical features of Alport syndrome and/or hematuria (PMID: 15618242; internal data). ClinVar contains an entry for this variant (Variation ID: 585525). Invitae Evidence 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 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 COL4A4 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. -
PP3, PM1, PM2 -
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. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -
Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A4 gene; 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: 15618242, 34400539) -
Autosomal recessive Alport syndrome;CN376803:Hematuria, benign familial, 1 Pathogenic:1
- -
COL4A4-related disorder Pathogenic:1
The COL4A4 c.1441G>A variant is predicted to result in the amino acid substitution p.Gly481Ser. This variant is reported in 0.061% of alleles in individuals of Latino descent in gnomAD. This variant affects a glycine (Gly) residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has been reported in an individual with an episode of macroscopic hematuria alongside persistent microhematuria and her affected mother (Frasca et al. 2005. PubMed ID: 15618242). In addition, at other glycine (Gly) residues within this domain, substitutions of a glycine (Gly) with a serine (Ser) have been widely reported to be pathogenic for autosomal recessive or dominant COL4A4 nephropathy (see for example, p.Gly1242Ser in Zhang et al. 2021. PubMed ID: 33772369, autosomal recessive Alport syndrome; p.Gly1201Ser in Fig. 4a of Mochizuki et al. 1994. PubMed ID: 7987396, autosomal recessive Alport syndrome; p.Gly748Ser in Papazachariou et al. 2017. PubMed ID: 28632965, autosomal dominant familial microscopic hematuria). Taken together, this variant is interpreted as pathogenic for both autosomal recessive and dominant COL4A4 nephropathy. -
not specified Uncertain:1
Variant summary: COL4A4 c.1441G>A (p.Gly481Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 249452 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (8.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.1441G>A has been reported in the literature in at least one individual affected with macroscopic haematuria with microhaematuria (Frasc_2004). The report does not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15618242, 36699462, 36292665). ClinVar contains an entry for this variant (Variation ID: 585525). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at