rs569681869

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000092.5(COL4A4):c.2320G>C(p.Gly774Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,613,980 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G774G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 5.10

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 2-227059468-C-G is Pathogenic according to our data. Variant chr2-227059468-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242442.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=1, Pathogenic=5}. Variant chr2-227059468-C-G is described in Lovd as [Pathogenic]. Variant chr2-227059468-C-G 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.2320G>C	p.Gly774Arg	missense_variant	Exon 28 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.2320G>C	p.Gly774Arg	missense_variant	Exon 28 of 48	5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000721

AC:

AN:

249564

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135398

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:

0.000425

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000911

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive Alport syndrome

Pathogenic:5

Oct 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A4 c.2320G>C (p.Gly774Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249564 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.2320G>C has been reported in the literature in multiple individuals affected with AD and AR Alport Syndrome (examples, Domingo-Gallego_2021, Kovacs_2016, Slajpah_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33532864, 26934356, 17396119). ClinVar contains an entry for this variant (Variation ID: 242442). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 17, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 20, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.85 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000242442 /PMID: 17396119).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 28632965).The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 28632965). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.2320G>C(p.Gly774Arg) in COL4A4 gene has been observed in heterozygous state in individual(s) with clinical features of autosomal dominant Alport syndrome, autosomal recessive Alport syndrome, and basement membrane disease (Kopadze et. al., 2021; Papazachariou et. al., 2017). It has also been observed to segregate with disease in related individuals. This variant has been reported in cis with the COL4A4 variant c.4394G>C, p.(Gly1465Asp) in individuals and families with both dominant and recessive forms of Alport syndrome (Goka et. al., 2021; Papazachariou et. al., 2017). The p.Gly774Arg variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.007% in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic / Uncertain Significance. The amino acid change p.Gly774Arg in COL4A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 774 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Alport syndrome

Pathogenic:3

Jan 09, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is homozygous for the c.2320G>C p.(Gly774Arg) variant in the COL4A4 gene. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.007% (19 out of 277,186 alleles). This variant has been previously reported in the heterozygous state in multiple members within a family with hematuria (Slajpah et al. Kidney Int 2007; 71: 1287-1295). The c.2320G>C results in the substitution of one of the invariant glycine residues in the triple helical domain p.(Gly774Arg). This variant is considered to be likely pathogenic according to the ACMG guidelines. -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with COL4A4-related nephropathy. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMID: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported. TBMN and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMID: 28704582, 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 19 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional G-X-Y triple-helical region (Uniprot). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with autosomal dominant Alport syndrome or haematuria. In addition, it is commonly reported to be in cis with a VUS (p.(Gly1465Asp)) (PMID: 26934356, 28632965, 17396119, 24854265). (SP) 0903 - This variant has limited evidence for segregation with disease. It has been reported in a single family with four affected individuals across two generations (PMID: 17396119). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in COL4A4 is predicted to replace glycine with arginine at codon 774 (p.(Gly774Arg)). The glycine residue is evolutionarily conserved (100 vertebrates, UCSC), and alters a critical glycine residue in a collagen triple helix repeat (Gly-X-Y) in one of the intermediate collagenous domains. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in gnomAD v2.1 is 0.04% (13/30,598 alleles) in the South Asian population, which is lower than the credible allele frequency for recessive Alport syndrome. This variant has been reported in cis with the variant of uncertain significance c.4394G>C, p.(Gly1465Asp) in individuals and families with both dominant and recessive forms of Alport syndrome (PMID: 24033287, 26934356, 28632965, 29496980, 33048202, 33838161). It has been reported alone heterozygous in at least one proband with haematuria and compound heterozygous for the variant and a pathogenic variant (confirmed in trans) in at least one proband with a clinical diagnosis of Alport syndrome (PMID: 24854265, 33532864). The variant has been reported to segregate alone with Alport syndrome with a dominant inheritance pattern in at least two families (PMID: 17396119, 28632965). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM3, PP1_Moderate, PM2_Supporting, PP3. -

not provided

Pathogenic:2Uncertain:1

Mar 30, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported with second variant on the opposite allele (in trans) in a two siblings with hematuria and thin basement membrane disease in published literature (Kovacs et al., 2016); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A4 gene; 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: 31589614, 33532864, 28632965, 24854265, 34400539, 34584596, 17396119, 26934356) -

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 774 of the COL4A4 protein (p.Gly774Arg). This variant is present in population databases (rs569681869, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of autosomal dominant Alport syndrome, autosomal recessive Alport syndrome, and basement membrane disease (PMID: 17396119, 26934356, 28632965, 33532864, 34584596). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242442). 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) indicates that this missense variant is expected to disrupt COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Jul 28, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_supporting, PM3_strong -

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

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Supporting+PM3+PP1_Strong+PP3+PP4 -

Benign familial hematuria

Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hematuria;C0020538:Hypertensive disorder;C0027092:Myopia;C0033687:Proteinuria;C1384666:Hearing impairment

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.2

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.96

Loss of methylation at R773 (P = 0.0358);

MVP

0.95

MPC

0.67

ClinPred

0.97

GERP RS

6.0

Varity_R

0.58

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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