rs104886124

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP3PP5

The NM_033380.3(COL4A5):​c.1587+1delG variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in Lovd as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 22)

Consequence

COL4A5
NM_033380.3 splice_donor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.27
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;
PP3
Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
PP5
Variant X-108597068-AG-A is Pathogenic according to our data. Variant chrX-108597068-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.1587+1delG splice_donor_variant, intron_variant ENST00000328300.11 NP_203699.1 P29400-2Q49AM6A7MBN3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkuse as main transcriptc.1587+1delG splice_donor_variant, intron_variant 1 NM_033380.3 ENSP00000331902.7 P29400-2
COL4A5ENST00000483338.1 linkuse as main transcriptc.411+1delG splice_donor_variant, intron_variant 1 ENSP00000495685.1 Q49AM6
COL4A5ENST00000361603.7 linkuse as main transcriptc.1587+1delG splice_donor_variant, intron_variant 2 ENSP00000354505.2 P29400-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.78
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.78
Position offset: 0

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: rs104886124; hg19: chrX-107840298; API