2-227284229-GAGTAAAGGGCC-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000091.5(COL4A3):βc.2768_2778delβ(p.Val923GlufsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000756 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. G922G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000091.5 frameshift
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 | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.2768_2778del | p.Val923GlufsTer13 | frameshift_variant | 34/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.244-2451_244-2441del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.2768_2778del | p.Val923GlufsTer13 | frameshift_variant | 34/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.244-2451_244-2441del | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249328Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135296
GnomAD4 exome AF: 0.0000814 AC: 119AN: 1461830Hom.: 0 AF XY: 0.0000770 AC XY: 56AN XY: 727228
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74320
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 11, 2023 | ClinVar contains an entry for this variant (Variation ID: 551819). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Alport syndrome (PMID: 24052634, 24854265). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs766306957, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Val923Glufs*13) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 20, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 2019 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30665703, 24052634, 24854265) - |
Autosomal recessive Alport syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 04, 2019 | Variant summary: COL4A3 c.2768_2778del11 (p.Val923GlufsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.4e-05 in 246024 control chromosomes (gnomAD). c.2768_2778del11 has been reported in the literature in homozygous and compound heterozygous individuals affected with Alport Syndrome, autosomal recessive (Storey 2013, Moriniere 2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 08, 2017 | - - |
Alport syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at