rs104886136

Variant summary

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

The NM_033380.3(COL4A5):​c.1681G>A​(p.Gly561Arg) 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 the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 22)

Consequence

COL4A5
NM_033380.3 missense

Scores

13
3
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.95
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, 0.984
PP5
Variant X-108597470-G-A is Pathogenic according to our data. Variant chrX-108597470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1520175.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108597470-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A5NM_033380.3 linkc.1681G>A p.Gly561Arg missense_variant Exon 24 of 53 ENST00000328300.11 NP_203699.1 P29400-2Q49AM6A7MBN3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkc.1681G>A p.Gly561Arg missense_variant Exon 24 of 53 1 NM_033380.3 ENSP00000331902.7 P29400-2
COL4A5ENST00000483338.1 linkc.505G>A p.Gly169Arg missense_variant Exon 8 of 20 1 ENSP00000495685.1 Q49AM6
COL4A5ENST00000361603.7 linkc.1681G>A p.Gly561Arg missense_variant Exon 24 of 51 2 ENSP00000354505.2 P29400-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Apr 29, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 sequence change replaces glycine with arginine at codon 561 of the COL4A5 protein (p.Gly561Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Alport syndrome (PMID: 10094548, Invitae). ClinVar contains an entry for this variant (Variation ID: 24435). 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
0.96
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.83
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
.;D;T
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.2
H;H;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-7.2
D;D;.
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
.;D;D
Vest4
0.99
MutPred
0.85
Loss of catalytic residue at G561 (P = 0.0528);Loss of catalytic residue at G561 (P = 0.0528);.;
MVP
1.0
MPC
0.36
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.85
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs104886136; hg19: chrX-107840700; API