rs104886240

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_033380.3(COL4A5):​c.3535G>A​(p.Gly1179Arg) 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. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1179V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

COL4A5
NM_033380.3 missense

Scores

13
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.36
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 Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_033380.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-108666577-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1493509.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant X-108666576-G-A is Pathogenic according to our data. Variant chrX-108666576-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.3535G>A p.Gly1179Arg missense_variant 39/53 ENST00000328300.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL4A5ENST00000328300.11 linkuse as main transcriptc.3535G>A p.Gly1179Arg missense_variant 39/531 NM_033380.3 P29400-2
COL4A5ENST00000361603.7 linkuse as main transcriptc.3535G>A p.Gly1179Arg missense_variant 39/512 P1P29400-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.83
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
.;D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.6
H;H
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.7
D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.033
D;D
Polyphen
1.0
.;D
Vest4
1.0
MutPred
0.99
Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);
MVP
1.0
MPC
0.36
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
1.0

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: rs104886240; hg19: chrX-107909806; API