rs104886443
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_033380.3(COL4A5):c.761_762del(p.Glu254ValfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
COL4A5
NM_033380.3 frameshift
NM_033380.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.96
Genes affected
COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. 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. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-108578361-TAG-T is Pathogenic according to our data. Variant chrX-108578361-TAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 587259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108578361-TAG-T is described in Lovd as [Pathogenic]. Variant chrX-108578361-TAG-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.761_762del | p.Glu254ValfsTer11 | frameshift_variant | 13/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.761_762del | p.Glu254ValfsTer11 | frameshift_variant | 13/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000361603.7 | c.761_762del | p.Glu254ValfsTer11 | frameshift_variant | 13/51 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 18, 2022 | This sequence change creates a premature translational stop signal (p.Glu254Valfs*11) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). For these reasons, this variant has been classified as Pathogenic. This variant is also known as Glu254-->frameshift. This premature translational stop signal has been observed in individual(s) with clinical features of Alport syndrome (PMID: 8738805, 33040356). This variant is not present in population databases (gnomAD no frequency). - |
X-linked Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 20, 2018 | - - |
Computational scores
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Calibrated prediction
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at