rs104886111

Positions:

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

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]

COL4A5 links:

Genome browser will be placed here

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
COL4A5	NM_033380.3 linkuse as main transcript	c.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	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.1276G>A	p.Gly426Arg	missense_variant	20/53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 linkuse as main transcript	c.100G>A	p.Gly34Arg	missense_variant	4/20	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 linkuse as main transcript	c.1276G>A	p.Gly426Arg	missense_variant	20/51	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

AN:

1096251

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

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:

AN:

112532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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 submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2022	PP2, PP3, PM1, PM2_supporting, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2021	Affects 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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This 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 submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 06, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Sep 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Oct 13, 2024	This 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 submitter	clinical testing	Revvity Omics, Revvity	Jul 23, 2021	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The 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 provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

The 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

BayesDel_noAF

Pathogenic

0.82

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;D;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;H;.

PrimateAI

Pathogenic

0.85

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over