chr2-227263944-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000091.5(COL4A3):c.1315G>A(p.Gly439Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000091.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.1315G>A | p.Gly439Ser | missense_variant, splice_region_variant | 21/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.1486+725C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.1315G>A | p.Gly439Ser | missense_variant, splice_region_variant | 21/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.1486+725C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461766Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727188
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant Alport syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 11, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2000 | - - |
Autosomal recessive Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 15, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 439 of the COL4A3 protein (p.Gly439Ser). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Alport syndrome (PMID: 11044206). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly493Ser. ClinVar contains an entry for this variant (Variation ID: 551759). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of skipping of exon 21, but is expected to preserve the integrity of the reading-frame (PMID: 11044206). For these reasons, this variant has been classified as Pathogenic. - |
Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 06, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at