rs281874671
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_033380.3(COL4A5):c.1589G>A(p.Gly530Asp) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 22)
Consequence
COL4A5
NM_033380.3 missense, splice_region
NM_033380.3 missense, splice_region
Scores
13
2
1
Splicing: ADA: 0.9432
1
1
Clinical Significance
Conservation
PhyloP100: 9.91
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 10 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_033380.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
?
Variant X-108597378-G-A is Pathogenic according to our data. Variant chrX-108597378-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38756.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108597378-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.1589G>A | p.Gly530Asp | missense_variant, splice_region_variant | 24/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.1589G>A | p.Gly530Asp | missense_variant, splice_region_variant | 24/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000483338.1 | c.413G>A | p.Gly138Asp | missense_variant, splice_region_variant | 8/20 | 1 | |||
COL4A5 | ENST00000361603.7 | c.1589G>A | p.Gly530Asp | missense_variant, splice_region_variant | 24/51 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
X-linked Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 05, 2021 | PM1, PM2, PP2, PP3, PP5 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
1.0
.;D;D
Vest4
MutPred
Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at