rs926605269
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000092.5(COL4A4):c.1405G>T(p.Gly469*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,613,470 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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151924Hom.: 0 Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461546Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727102
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151924Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74168
ClinVar
Submissions by phenotype
Autosomal recessive Alport syndrome Pathogenic:1
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not provided Pathogenic:1
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 553870). This premature translational stop signal has been observed in individual(s) with clinical features of Alport syndrome (PMID: 15954103). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly469*) 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). For these reasons, this variant has been classified as Pathogenic. -
Autosomal dominant Alport syndrome Pathogenic:1
This sequence change in COL4A4 is a nonsense variant predicted to cause a premature stop codon (p.(Gly469*)) in biologically-relevant-exon 21/48 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 20301386). This variant is present in a single European (non-Finnish) individual in gnomAD v2.1 (1/67,998 alleles). This variant has been reported in at least two probands with a phenotype consistent with autosomal dominant Alport syndrome (PMID: 15954103; Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Supporting, PM2_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at