rs281874681
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate
The NM_033380.3(COL4A5):c.1856C>T(p.Pro619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P619S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 23)
Consequence
COL4A5
NM_033380.3 missense
NM_033380.3 missense
Scores
1
6
10
Clinical Significance
Conservation
PhyloP100: 2.39
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 6 ACMG points.
PM1
In a compositionally_biased_region Pro residues (size 22) in uniprot entity CO4A5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_033380.3
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-108598778-C-T is Pathogenic according to our data. Variant chrX-108598778-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2138696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108598778-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-108598778-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.1856C>T | p.Pro619Leu | missense_variant | 25/53 | ENST00000328300.11 | NP_203699.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.1856C>T | p.Pro619Leu | missense_variant | 25/53 | 1 | NM_033380.3 | ENSP00000331902.7 | ||
COL4A5 | ENST00000483338.1 | c.680C>T | p.Pro227Leu | missense_variant | 9/20 | 1 | ENSP00000495685.1 | |||
COL4A5 | ENST00000361603.7 | c.1856C>T | p.Pro619Leu | missense_variant | 25/51 | 2 | ENSP00000354505.2 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 14, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 619 of the COL4A5 protein (p.Pro619Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 11462238, 17660027, 19728970). It has also been observed to segregate with disease in related individuals. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL4A5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
.;D;T
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;N;.
REVEL
Uncertain
Sift
Benign
T;T;.
Sift4G
Benign
T;T;.
Polyphen
0.0080, 0.0030
.;B;B
Vest4
MutPred
Loss of glycosylation at P623 (P = 0.2517);Loss of glycosylation at P623 (P = 0.2517);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 30
Find out detailed SpliceAI scores and Pangolin per-transcript scores at