rs104886111

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_033380.3(COL4A5):​c.1276G>A​(p.Gly426Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,208,783 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

13
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.42
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 16 ACMG points.

PM1
In a compositionally_biased_region Pro residues (size 47) in uniprot entity CO4A5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_033380.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant X-108591168-G-A is Pathogenic according to our data. Variant chrX-108591168-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108591168-G-A is described in Lovd as [Pathogenic]. Variant chrX-108591168-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.1276G>A p.Gly426Arg missense_variant 20/53 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.1276G>A p.Gly426Arg missense_variant 20/531 NM_033380.3 ENSP00000331902.7 P29400-2
COL4A5ENST00000483338.1 linkuse as main transcriptc.100G>A p.Gly34Arg missense_variant 4/201 ENSP00000495685.1 Q49AM6
COL4A5ENST00000361603.7 linkuse as main transcriptc.1276G>A p.Gly426Arg missense_variant 20/512 ENSP00000354505.2 P29400-1

Frequencies

GnomAD3 genomes
AF:
0.00000889
AC:
1
AN:
112532
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34710
show subpopulations
Gnomad AFR
AF:
0.0000322
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
3
AN:
1096251
Hom.:
0
Cov.:
30
AF XY:
0.00000276
AC XY:
1
AN XY:
362499
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000356
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000889
AC:
1
AN:
112532
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34710
show subpopulations
Gnomad4 AFR
AF:
0.0000322
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitterresearchGharavi Laboratory, Columbia UniversitySep 16, 2018- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 03, 2022PP2, PP3, PM1, PM2_supporting, PS4_moderate -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 08, 2021Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15954103, 21505094, 30647093) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 05, 2023This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 426 of the COL4A5 protein (p.Gly426Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 15954103, 21505094, 30647093; Invitae). ClinVar contains an entry for this variant (Variation ID: 24393). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. -
X-linked Alport syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 06, 2024- -
Pathogenic, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic HealthcareSep 25, 2019- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterOct 13, 2024This variant (GRCh38; NM_033380.3:c.1276G>A:p.Gly426Arg) results in a missense mutation with the conversion of Glycine (Polar amino acid) to Arginine (Basic amino acid) in the COL4A5 protein. Located in a mutational hot spot and/or critical and well established functional domain without benign variation. Not observed at significant frequency in large population cohorts (gnomAD). This variant has a strong Conservation score. Multiple lines of computational evidence support a deleterious effect on the gene or gene product for this variant. ClinVar contains an entry for this variant (Variation ID: 24393). This variant is associated with the following publications: PubMed: 21505094, 15954103, 23720012, 29526710, 30586318, 27627812 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJul 23, 2021- -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 28, 2023The c.1276G>A (p.G426R) alteration is located in exon 20 (coding exon 20) of the COL4A5 gene. This alteration results from a G to A substitution at nucleotide position 1276, causing the glycine (G) at amino acid position 426 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in multiple individuals with clinical features of COL4A5-related Alport syndrome (Zhou, 2023; Shulman, 2021; Groopman, 2019; Yao, 2019; Ma, 2011; Nagel, 2005). This amino acid position is highly conserved in available vertebrate species. In an assay testing COL4A5 function, this variant showed a functionally abnormal result (Omachi, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
COL4A5-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 04, 2024The COL4A5 c.1276G>A variant is predicted to result in the amino acid substitution p.Gly426Arg. The p.Gly426Arg residue resides in the triple-helical domain (residues 42 – 1456; uniprot.org) of the COL4A5 protein where substitutions of the glycine (Gly) residue are usually expected to be pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has been reported in individuals with Alport syndrome and/or focal segmental glomerulosclerosis (see for example, Nagel et al. 2005. PubMed ID: 15954103; Supp. Table 7 in Groopman et al. 2018. PubMed ID: 30586318; Yao et al. 2019. PubMed ID: 30647093). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.82
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
.;D;D
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.7
H;H;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.5
D;D;.
REVEL
Pathogenic
1.0
Sift
Uncertain
0.0010
D;D;.
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
.;D;D
Vest4
0.99
MutPred
0.98
Gain of solvent accessibility (P = 6e-04);Gain of solvent accessibility (P = 6e-04);.;
MVP
1.0
MPC
0.36
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.98

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: rs104886111; hg19: chrX-107834398; COSMIC: COSV60358773; API