rs104886431
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePP3_StrongPP5_Moderate
The NM_033380.3(COL4A5):c.547-1G>A variant causes a splice acceptor change. 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
COL4A5
NM_033380.3 splice_acceptor
NM_033380.3 splice_acceptor
Scores
3
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.09
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.012214342 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of 1, new splice context is: tttactcactttataacaAGgcc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
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-108575909-G-A is Pathogenic according to our data. Variant chrX-108575909-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2627802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108575909-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.547-1G>A | splice_acceptor_variant | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.547-1G>A | splice_acceptor_variant | 1 | NM_033380.3 | ||||
COL4A5 | ENST00000361603.7 | c.547-1G>A | splice_acceptor_variant | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1051761Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 327059
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1051761
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Cov.:
24
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AC XY:
0
AN XY:
327059
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
Alfa
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 15, 2023 | This sequence change affects an acceptor splice site in intron 9 of the COL4A5 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 COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Alport syndrome (PMID: 11462238, 20378821). This variant is also known as c.749-1G>A. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
X-linked Alport syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Department, Charles Nicolle Hospital Tunis | Sep 05, 2022 | DNA sequencing revealed a novel hemizygous splicing mutation, NM_000495: c.547-1G>A, in three males from a Tunisian family. This splicing mutation, NM_000495: c.547-1G>A, was not found in the NHLBI Exome Variant Server or the ClinVar database. Analysis of NM_000495: c.547-1G>A using Alamut predicted a highly probable exon 10 skipping. The segregation pattern is consistent with an X-linked dominant mode. Notably, this novel mutation was absent in 50 control Tunisian samples. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
GERP RS
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: 2
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at