rs766550724

Variant names:

Variant summary

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

The NM_000092.5(COL4A4):c.5044C>T(p.Arg1682Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1682Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 0.860

Variant links:

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a disulfide_bond Or C-1588 with C-1683 (size 98) in uniprot entity CO4A4_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000092.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-227007353-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 2-227007354-G-A is Pathogenic according to our data. Variant chr2-227007354-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552827.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4}. Variant chr2-227007354-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.5044C>T	p.Arg1682Trp	missense_variant	Exon 48 of 48	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.5044C>T	p.Arg1682Trp	missense_variant	Exon 48 of 48	5	NM_000092.5	ENSP00000379866.3		P53420
COL4A4	ENST00000682098.1 link	c.646C>T	p.Arg216Trp	missense_variant	Exon 3 of 3			ENSP00000508331.1		A0A804HLF6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249586

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135406

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727248

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000922

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Jul 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL4A4 c.5044C>T; p.Arg1682Trp variant (rs766550724, ClinVar Variation ID: 552827) is reported in the literature in multiple individuals affected with symptoms of Alport syndrome or familial benign hematuria, though additional evidence of causality was not provided (Artuso 2012, Yuan 2023, Topak 2024). This variant is only observed on three alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.920). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Artuso R et al. Advances in Alport syndrome diagnosis using next-generation sequencing. Eur J Hum Genet. 2012 Jan;20(1):50-7PMID: 21897443 Yuan X et al. Genetic Variants of the COL4A3 , COL4A4 , and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients. J Am Soc Nephrol. 2023 Jan 1;34(1):132-144. PMID: 36130833. Topak A. Molecular diagnostic results of a nephropathy gene panel in patients with suspected hereditary kidney disease. Lab Med. 2024 Jan 6;55(1):13-19. PMID: 37078890. Savige J et al. Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. Eur J Hum Genet. 2021 Aug;29(8):1186-1197. PMID: 33854215. Uliana V et al. Deciphering the pathogenesis of the COL4-related hematuric nephritis: A genotype/phenotype study. Mol Genet Genomic Med. 2021 Feb;9(2):e1576. PMID: 33369211. Gene Statement: Pathogenic COL4A4 variants are associated with autosomal dominant familial benign hematuria (MIM: 141200) and autosomal recessive Alport syndrome 2 (MIM: 203780). Autosomal dominant COL4A4-related conditions are clinically variable and can range from isolated non-progressive hematuria to a slowly progressive disorder with renal insufficiency and sensorineural hearing loss (SNHL) developing later in life. Autosomal recessive COL4A3-related Alport syndrome, caused by biallelic pathogenic variants, is typically more severe and characterized by an earlier age of onset of both SNHL and renal failure (Uliana 2021 and Savige 2021). -

Oct 30, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21897443) -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1682 of the COL4A4 protein (p.Arg1682Trp). This variant is present in population databases (rs766550724, gnomAD 0.003%). This missense change has been observed in individual(s) with Alport syndrome and/or clinical features of COL4A4-related conditions (PMID: 21897443, 36130833, 37078890; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 552827). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A4 protein function. This variant disrupts the p.Arg1682 amino acid residue in COL4A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17216251, 26809805, 27859054). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Autosomal recessive Alport syndrome

Uncertain:2

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive Alport syndrome;CN376803:Hematuria, benign familial, 1

Pathogenic:1

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Alport syndrome

Pathogenic:1

Jul 12, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.77

MutPred

0.77

Loss of disorder (P = 0);

MVP

0.89

MPC

0.15

ClinPred

1.0

GERP RS

2.0

Varity_R

0.93

gMVP

0.83

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