rs104886068

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM2PP3_StrongPP5_Moderate

The NM_033380.3(COL4A5):​c.716G>A​(p.Gly239Glu) 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 ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 23)

Consequence

COL4A5
NM_033380.3 missense

Scores

13
3
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.06
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 Pathogenic. Variant got 10 ACMG points.

PS1
Transcript NM_033380.3 (COL4A5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant X-108578319-G-A is Pathogenic according to our data. Variant chrX-108578319-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2737327.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108578319-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.716G>A p.Gly239Glu missense_variant 13/53 ENST00000328300.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL4A5ENST00000328300.11 linkuse as main transcriptc.716G>A p.Gly239Glu missense_variant 13/531 NM_033380.3 P29400-2
COL4A5ENST00000361603.7 linkuse as main transcriptc.716G>A p.Gly239Glu missense_variant 13/512 P1P29400-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2023This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 239 of the COL4A5 protein (p.Gly239Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alport syndrome (PMID: 8940267). 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 expected to disrupt COL4A5 protein function. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.82
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.73
.;D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.6
H;H
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.1
D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
.;D
Vest4
0.96
MutPred
0.83
Loss of catalytic residue at G239 (P = 0.0308);Loss of catalytic residue at G239 (P = 0.0308);
MVP
1.0
MPC
0.39
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
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: rs104886068; hg19: chrX-107821549; API