X-108692786-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_033380.3(COL4A5):​c.4567C>G​(p.Pro1523Ala) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Consequence

COL4A5
NM_033380.3 missense

Scores

15
1
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91
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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_033380.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.4567C>G p.Pro1523Ala missense_variant 50/53 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.4567C>G p.Pro1523Ala missense_variant 50/531 NM_033380.3 ENSP00000331902.7 P29400-2

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.66
D
BayesDel_noAF
Pathogenic
0.71
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
.;D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
.;H
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-7.8
D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.87
MutPred
0.82
.;Gain of catalytic residue at P1517 (P = 0.046);
MVP
0.95
MPC
1.0
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.97
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs201220208; hg19: chrX-107936016; API