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

Genomes: not found (cov: 23)
Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

COL4A5
ENST00000328300.11 splice_acceptor

Scores

3
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.85
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03289992 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.2, offset of -31, new splice context is: atcttttaaaactgcttcAGtac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-108620257-A-G is Pathogenic according to our data. Variant chrX-108620257-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562406.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108620257-A-G 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.2510-2A>G splice_acceptor_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.2510-2A>G splice_acceptor_variant 1 NM_033380.3 ENSP00000331902 P29400-2
COL4A5ENST00000483338.1 linkuse as main transcriptc.1334-2A>G splice_acceptor_variant 1 ENSP00000495685
COL4A5ENST00000361603.7 linkuse as main transcriptc.2510-2A>G splice_acceptor_variant 2 ENSP00000354505 P1P29400-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.00000552
AC:
1
AN:
181241
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
67067
show subpopulations
Gnomad AFR exome
AF:
0.0000763
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
9.23e-7
AC:
1
AN:
1083682
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
350646
show subpopulations
Gnomad4 AFR exome
AF:
0.0000383
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 22, 2020In 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 providedresearchGharavi Laboratory, Columbia UniversitySep 16, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
34
DANN
Uncertain
1.0
FATHMM_MKL
Pathogenic
1.0
D
MutationTaster
Benign
1.0
D;D
GERP RS
6.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.89
Position offset: 20
DS_AL_spliceai
1.0
Position offset: 2

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: rs760109866; hg19: chrX-107863487; API