chr2-227102759-TCACTGATGTTAACAGCAAATGATGCTTACCCGAGGCCCTGGAAATC-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000092.5(COL4A4):c.914_930+29del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,585,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
COL4A4
NM_000092.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
NM_000092.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.35
Genes affected
COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.011630199 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of -4, new splice context is: ctgGTattg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-227102759-TCACTGATGTTAACAGCAAATGATGCTTACCCGAGGCCCTGGAAATC-T is Pathogenic according to our data. Variant chr2-227102759-TCACTGATGTTAACAGCAAATGATGCTTACCCGAGGCCCTGGAAATC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A4 | NM_000092.5 | c.914_930+29del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 15/48 | ENST00000396625.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A4 | ENST00000396625.5 | c.914_930+29del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 15/48 | 5 | NM_000092.5 | P1 | ||
COL4A4 | ENST00000643379.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000140 AC: 2AN: 1433040Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 715150
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74350
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2023 | This variant results in the deletion of part of exon 15 (c.914_930+29del) of the COL4A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Alport syndrome (PMID: 9792860; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 1122del46bp. ClinVar contains an entry for this variant (Variation ID: 447196). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2022 | Canonical splice site variant predicted to result in in-frame deletion within a critical region. Variant damages or destroys the canonical splice donor site in intron 15, and is expected to cause abnormal gene splicing; if the splice outcome is exon skip, the loss of the encoded residues in the triple helical region is expected to disrupt normal protein folding and function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9792860) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 21, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 01, 2022 | - - |
Autosomal recessive Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at