rs533297350

Positions:

chr2-227010441-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000092.5(COL4A4):c.4394G>A(p.Gly1465Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,458 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).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:6

Conservation

PhyloP100: 7.86

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 6 ACMG points.

PM1

In a domain Collagen IV NC1 (size 225) in uniprot entity CO4A4_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) in NM_000092.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.4394G>A	p.Gly1465Asp	missense_variant	46/48	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.4394G>A	p.Gly1465Asp	missense_variant	46/48	5	NM_000092.5	ENSP00000379866.3		P53420
COL4A4	ENST00000682098.1 link	c.61G>A	p.Ala21Thr	missense_variant	1/3			ENSP00000508331.1		A0A804HLF6

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152252

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:

0.0000725

AC:

AN:

248434

Hom.:

AF XY:

0.0000816

AC XY:

AN XY:

134748

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:

0.000426

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461206

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726812

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:

0.000487

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74382

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:5Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive Alport syndrome

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 02, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.4394G>A(p.Gly1465Asp) 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 is almost always reported in cis with the COL4A4 variant c.2320G>C, p.(Gly774Arg) in individuals and families with both dominant and recessive forms of Alport syndrome (Goka et. al., 2021; Papazachariou et. al., 2017). The p.Gly1465Asp 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.Gly1465Asp in COL4A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 1465 is changed to a Asp 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

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. 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 aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 19 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated collagen IV NC1 domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been classified as likely pathogenic and a VUS by diagnostic laboratories in ClinVar, likely because it has been reported to be in cis with a known pathogenic variant (p.(Gly774Arg)). However, a single family has been reported with Alports disease, where no other variant was detected (ClinVar; PMID: 28632965, 26934356, 24033287). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 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 -
Uncertain significance, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Jan 09, 2018	This individual is also homozygous for the c.4394G>A p.(Gly1465Asp) variant in the COL4A4 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. The c.4394G>A variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.006% (19 out of 275976 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in COL4A4 is predicted to replace glycine with aspartic acid at codon 1465 (p.(Gly1465Asp)). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the collagen IV NC1 domain. There is a moderate physicochemical difference between glycine and aspartic acid. The highest population minor allele frequency in gnomAD v2.1 is 0.04% (13/30,488 alleles) in the South Asian population, which is lower than the credible allele frequency for recessive Alport syndrome. This variant is almost always reported in cis with the likely pathogenic variant c.2320G>C, p.(Gly774Arg) in individuals and families with both dominant and recessive forms of Alport syndrome (PMID: 24033287, 26934356, 28632965, 29496980, 33048202, 33838161). 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 a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 27, 2021	BP2, PP3, PM2_supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1465 of the COL4A4 protein (p.Gly1465Asp). This variant is present in population databases (rs533297350, 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: 24033287, 26934356, 28632965, 34584596). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 523324). 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 COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Benign familial hematuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PS4_Supporting+PP3+PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.67

Gain of sheet (P = 0.1208);

MVP

0.94

MPC

0.18

ClinPred

0.82

GERP RS

5.7

Varity_R

0.54

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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