rs876657397
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000091.5(COL4A3):βc.40_63delβ(p.Leu14_Leu21del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000557 in 1,525,760 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. Q10Q) has been classified as Likely benign.
Frequency
Consequence
NM_000091.5 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.40_63del | p.Leu14_Leu21del | inframe_deletion | 1/52 | ENST00000396578.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.40_63del | p.Leu14_Leu21del | inframe_deletion | 1/52 | 1 | NM_000091.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 151956Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000140 AC: 17AN: 121044Hom.: 0 AF XY: 0.000165 AC XY: 11AN XY: 66524
GnomAD4 exome AF: 0.0000597 AC: 82AN: 1373804Hom.: 0 AF XY: 0.0000694 AC XY: 47AN XY: 677680
GnomAD4 genome AF: 0.0000197 AC: 3AN: 151956Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74228
ClinVar
Submissions by phenotype
Autosomal recessive Alport syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 28570636, 23927549, 22887978, PM3_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 28570636, PS3_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000192299).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000140, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 06, 2019 | Variant summary: COL4A3 c.40_63del24 (p.Leu14_Leu21del) results in an in-frame deletion that is predicted to remove eight amino acids from the COL4A3 signal peptide sequence of the encoded protein. The variant allele was found at a frequency of 0.00022 in 125078 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in COL4A3 causing autosomal recessive Alport Syndrome (0.00022 vs 0.002), allowing no conclusion about variant significance. c.40_63del24 has been reported in the literature in multiple individuals affected with autosomal recessive Alport Syndrome worldwide (Zhang_2012, Oka_2014, Webb_2014, Chiereghin_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a disruption of COL4A3 signal peptide, possibly altering protein secretion (Chiereghin_2017). No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This variant, c.40_63del, results in the deletion of 8 amino acid(s) of the COL4A3 protein (p.Leu14_Leu21del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs774798108, gnomAD 0.1%). This variant has been observed in individuals with Alport syndrome (PMID: 23927549, 28570636). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 192299). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects COL4A3 function (PMID: 28570636). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2022 | Published with a carrier frequency within the Ashkenazi Jewish population of 1 in 183, and may be a founder variant for Alport syndrome in this population (Webb et al., 2014); Published in vitro studies demonstrate that the deletion alters the COL4A3 signal peptide and changes the subcellular protein localization; variant results in diffuse localization in the cytoplasm and nucleus (Chiereghin et al., 2017); In-frame deletion of 8 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 33772369, 12028435, 14582039, 22887978, 23927549, 28570636, 24633401, 29801666) - |
COL4A3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 10, 2023 | The COL4A3 c.40_63del24 variant is predicted to result in an in-frame deletion (p.Leu14_Leu21del). This variant has been reported to be pathogenic for Alport syndrome (AS) (in the homozygous state), and microhematuria/mild proteinuria (in the heterozygous state) (Webb et al. 2014. PubMed ID: 23927549; Longo et al. 2002. PubMed ID: 12028435; Chiereghin et al. 2017. PubMed ID: 28570636). In particular, this deletion was reported to be a pathogenic founder variant in the Ashkenazi Jewish population. This variant is reported in 0.13% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-228029471-AGGTGCTCCTGCTGCCGCTCCTGCT-A). This variant is interpreted as pathogenic. - |
Alport syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 20, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at