rs760109866
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The ENST00000328300.11(COL4A5):c.2510-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000923 in 1,083,682 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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
ENST00000328300.11 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.2510-2A>G | splice_acceptor_variant | ENST00000328300.11 | NP_203699.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.2510-2A>G | splice_acceptor_variant | 1 | NM_033380.3 | ENSP00000331902 | ||||
COL4A5 | ENST00000483338.1 | c.1334-2A>G | splice_acceptor_variant | 1 | ENSP00000495685 | |||||
COL4A5 | ENST00000361603.7 | c.2510-2A>G | splice_acceptor_variant | 2 | ENSP00000354505 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 exomes AF: 0.00000552 AC: 1AN: 181241Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67067
GnomAD4 exome AF: 9.23e-7 AC: 1AN: 1083682Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 350646
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 22, 2020 | 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with COL4A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 562406). This variant is present in population databases (rs760109866, ExAC 0.01%). This sequence change affects an acceptor splice site in intron 30 of the COL4A5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at