rs534522842
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000092.5(COL4A4):c.1045C>T(p.Arg349Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,290 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000092.5 stop_gained
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL4A4 | NM_000092.5 | c.1045C>T | p.Arg349Ter | stop_gained | 18/48 | ENST00000396625.5 | NP_000083.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL4A4 | ENST00000396625.5 | c.1045C>T | p.Arg349Ter | stop_gained | 18/48 | 5 | NM_000092.5 | ENSP00000379866 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249414Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135318
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74464
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg349*) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is present in population databases (rs534522842, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Alport syndrome (PMID: 33532864). ClinVar contains an entry for this variant (Variation ID: 447178). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 01, 2021 | - - |
Autosomal recessive Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
Nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Jan 09, 2018 | This individual is heterozygous for the c.1045C>T p.(Arg349*) variant in the COL4A4 gene. This variant creates a premature stop codon p.(Arg349*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.0004% (1 out of 246, 064 alleles). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. However, other truncating variants downstream of this amino acid have been described in ClinVar. This variant is considered to be a likely pathogenic according to the ACMG guidelines. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at