rs377511303
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000092.5(COL4A4):c.410G>A(p.Gly137Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,648 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. G137S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000092.5 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 |
---|---|---|---|---|---|---|---|
COL4A4 | NM_000092.5 | c.410G>A | p.Gly137Asp | missense_variant | 7/48 | ENST00000396625.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A4 | ENST00000396625.5 | c.410G>A | p.Gly137Asp | missense_variant | 7/48 | 5 | NM_000092.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152152Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248802Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135028
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461648Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727156
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 05, 2022 | Variant summary: COL4A4 c.410G>A (p.Gly137Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of 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 8e-06 in 248802 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.410G>A has been reported in the literature in heterozygous individuals affected with kidney disease (Malone_2015, Varner_2018), however, these reports do 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. Three ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Autosomal recessive Alport syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 27, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces glycine with aspartic acid at codon 137 of the COL4A4 protein (p.Gly137Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with focal segmental glomerulosclerosis or steroid resistant nephrotic syndrome (PMID: 25229338, 30406062). ClinVar contains an entry for this variant (Variation ID: 551248). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Alport syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 15, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at