rs397515497
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_033380.3(COL4A5):c.3107-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
COL4A5
NM_033380.3 splice_region, splice_polypyrimidine_tract, intron
NM_033380.3 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9948
2
Clinical Significance
Conservation
PhyloP100: 3.35
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant X-108626206-A-G is Pathogenic according to our data. Variant chrX-108626206-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1465065.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.3107-4A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.3107-4A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_033380.3 | ||||
COL4A5 | ENST00000483338.1 | c.1931-4A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | |||||
COL4A5 | ENST00000361603.7 | c.3107-4A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 2 | P1 | ||||
COL4A5 | ENST00000505728.1 | c.340-4A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
Alfa
AF:
Hom.:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant is associated with the activation of a cryptic splice site in intron 35 (PMID: 21505094). This variant has been observed in individual(s) with clinical features of Alport syndrome (PMID: 29959198, 21505094). ClinVar contains an entry for this variant (Variation ID: 38773). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 35 of the COL4A5 gene. It does not directly change the encoded amino acid sequence of the COL4A5 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of one amino acid residue(s), but is expected to preserve the integrity of the reading-frame. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at