rs281874721
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_033380.3(COL4A5):c.3722G>A(p.Gly1241Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1241C) has been classified as Pathogenic.
Frequency
Consequence
NM_033380.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.3722G>A | p.Gly1241Asp | missense_variant | 41/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.3722G>A | p.Gly1241Asp | missense_variant | 41/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000361603.7 | c.3722G>A | p.Gly1241Asp | missense_variant | 41/51 | 2 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 11, 2019 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine with aspartic acid at codon 1241 of the COL4A5 protein (p.Gly1241Asp). 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 variant has not been reported in the literature in individuals with COL4A5-related conditions. This variant disrupts the p.Gly1241 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 7599631, 20378821), which suggests that this may be a clinically significant amino acid residue. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). - |
Nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Nov 10, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at