rs587776404

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The ENST00000328300.11(COL4A5):​c.4821+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 22)

Consequence

COL4A5
ENST00000328300.11 splice_donor

Scores

3
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.97
Variant links:
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 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-108694922-G-A is Pathogenic according to our data. Variant chrX-108694922-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 24775.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108694922-G-A is described in Lovd as [Pathogenic]. Variant chrX-108694922-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.4821+1G>A splice_donor_variant ENST00000328300.11 NP_203699.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkuse as main transcriptc.4821+1G>A splice_donor_variant 1 NM_033380.3 ENSP00000331902 P29400-2

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
24
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 22, 2019For these reasons, this variant has been classified as 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). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 8940267). This variant has been observed in an individual affected with X-linked Alport syndrome (PMID: 8940267). This variant is also known as c.5005+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 24775). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 49 of the COL4A5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
31
DANN
Uncertain
1.0
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
D;D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.71
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.71
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776404; hg19: chrX-107938152; API