rs200302125

Positions:

chr2-227307878-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP3BP4_StrongBS1_SupportingBS2

The NM_000091.5(COL4A3):c.4421T>C(p.Leu1474Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,614,166 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 23 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:14B:7

Conservation

PhyloP100: 7.67

Variant links:

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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. [provided by RefSeq, Jun 2010]

COL4A3 links:

MFF-DT (HGNC:):

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A3_HUMAN there are 24 pathogenic changes around while only 2 benign (92%) in NM_000091.5

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.038383782).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0046 (6724/1461862) while in subpopulation NFE AF= 0.00577 (6415/1111988). AF 95% confidence interval is 0.00565. There are 23 homozygotes in gnomad4_exome. There are 3231 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 23 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.4421T>C	p.Leu1474Pro	missense_variant	48/52	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.4421T>C	p.Leu1474Pro	missense_variant	48/52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

372

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00270

AC:

673

AN:

249412

Hom.:

AF XY:

0.00259

AC XY:

350

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.000775

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00460

AC:

6724

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00444

AC XY:

3231

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.00577

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.00244

AC:

372

AN:

152304

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00389

Hom.:

Bravo

AF:

0.00267

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000793

AC:

ESP6500EA

AF:

0.00414

AC:

ExAC

AF:

0.00275

AC:

332

EpiCase

AF:

0.00513

EpiControl

AF:

0.00439

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:14Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 21, 2024	PP3, PM3 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL4A3: PM3:Strong, PM2:Supporting -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2024	Reported previously in association with COL4A3-related disorders and also reported as a polymorphism (PMID: 24130771, 25307543, 26346198, 12028435, 14871398); 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: 30819905, 14871398, 17216251, 31865346, 26809805, 24130771, 36117978, 12028435, 7987301, 29924831, 9269635, 11044206, 31027891, 11961012, 14582039, 27932480, 21897443, 30406062, 25229338, 29271581, 28658201, 31903434, 33391746, 31256874, 26346198, 25307543, 30295827, 29204651, 31477057, 32887937, 34426522, 33040356, 32939031, 34013111, 33654185, 35602506, 35260866, 36134775, 11134255, 36100708, 35090027, 37163122, Venda2023[Abstract], 37895316, 37915894) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 22, 2023	- -

Autosomal recessive Alport syndrome

Pathogenic:2Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 14, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 18, 2023	PS3_Moderate, PM3_Strong, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Apr 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Nov 01, 2022	- -

Autosomal dominant Alport syndrome

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Jun 14, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 10, 2023	Criteria applied: PP3 -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	May 01, 2024	Pathogenic by Deafness Variation Database and by ClinVar based on PMID: 31477057. -

Alport syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL4A3-related nephropathy. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435). (I) 0108 - This gene is associated with both recessive (Alport syndrome 2 MIM#203780) and dominant disease (Alport syndrome 3 MIM#104200 and benign familial hematuria MIM#141200) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (748 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) 0600 - Variant is located in the annotated C4 domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported with conflicting classifications from benign to pathogenic. Although this variant has been reported in both heterozygous and compound heterozygous states in multiple patients with renal conditions, there is still uncertainty surrounding its contribution to disease (ClinVar, LOVD, Decipher, PMID: 31477057, 32887937). (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, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Dec 11, 2020	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2020	- -

COL4A3-related disorder

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 07, 2024	The COL4A3 c.4421T>C variant is predicted to result in the amino acid substitution p.Leu1474Pro. In the compound heterozygous state with another pathogenic COL4A3 variant, the c.4421T>C (p.Leu1474Pro) variant has been reported in patients with autosomal recessive Alport syndrome or early progression to end-stage renal disease (Chatterjee et al. 2013. PubMed ID: 24130771; Gast et al. 2015. PubMed ID: 26346198; Nabais Sá et al. 2015. PubMed ID: 25307543; Boeckhaus et al. 2020. PubMed ID: 33040356). Of note, in the Chatterjee et al. study, the p.Leu1474Pro variant in the heterozygous state was also found in an unaffected brother and his son with unknown disease status. This variant in the heterozygous state has been repeatedly reported in patients with focal segmental glomerulosclerosis (Feltran et al. 2017. PubMed ID: 28658201; Gast et al. 2015. PubMed ID: 26346198; Malone et al. 2014. PubMed ID: 25229338). This variant was also reported in one patient with cervical artery dissection (Traenka et al. 2019. PubMed ID: 31903434). Furthermore, this variant along with a rare COL4A4 variant was reported in an identical twin brother-pair with cervical artery dissection (Brandt et al. 2018. PubMed ID: 29271581). This variant was reported in two siblings with IgA Nephropathy as variant of uncertain significance (Stapleton et al. 2020. PubMed ID: 31865346). However, the minor allele frequency of this variant in the general population reaches ~0.5%, which could be too high to be a primary cause of autosomal dominant COL4A3-related disease. Of note, incomplete penetrance has been reported in COL4A3-related disorders (Pescucci et al. 2004. PubMed ID: 15086897). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 17, 2018	The COL4A3 c.4421T>C (p.Leu1474Pro) variant has been reported in at least five studies and is found in a total of nine probands, including five probands with clinical symptoms of Alport syndrome, two of which are siblings, in a compound heterozygous state and four proband in a heterozygous state, including one sibling pair (Chatterjee et al. 2013; Nabais Sa et al. 2015; Gast et al. 2016; Bierzynska et al. 2017; Brandt et al. 2018). This included two compound heterozygous probands with end stage renal disease (Nabais Sa et al. 2015). The remaining three compound heterozygous probands were identified to have variants in additional genes known to be associated with glomerulopathy (Chatterjee et al. 2013; Gast et al. 2016). The c.4421T>C (p.Leu1474Pro) variant was also observed in a presumed heterozygous state in the unaffected brother of a compound heterozygote and this brother's son (Chatterjee et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.004899 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Leu1474Pro variant is classified as likely pathogenic for COL4A3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2022	Variant summary: COL4A3 c.4421T>C (p.Leu1474Pro) results in a non-conservative amino acid change located in the non-collagenous domain (IPR001442) of 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 0.0027 in 249412 control chromosomes, predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.6-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive phenotype (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.4421T>C, has been reported in the literature in several individuals affected with Alport Syndrome, focal segmental glomerulosclerosis (FSGS), steroid-resistant nephrotic syndrome (SRNS) and other nephrotic phenotypes, however without strong evidence for causality (e.g. Lemmink_1994, VanDerLoop_2000, Heidet_2001, Vega_2003, Chatterjee_2013, Malone_2014, Gast_2016, Weber_2016, Bierzynska_2017, Lata_2018), several of these reports described the variant as polymorphism, and in some of the reported cases atypical findings for Alport Syndrome were noted, or co-occurring variants in COL4A3 (with dominant mode of inheritance) or other genes could potentially explain the phenotype. These reports do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eighteen submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant with conflicting assessments, as pathogenic (n=1) / likely pathogenic (n=3), VUS (n=8), likely benign (n=4) / benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 15, 2020	The p.Leu1474Pro variant in COL4A3 is classified as benign because it has been identified in 0.5% (627/128566) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Hearing impairment

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Strong, PM2_Moderate, PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.038

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.0

D;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.98

MVP

0.97

MPC

0.30

ClinPred

0.088

GERP RS

5.9

Varity_R

0.96

gMVP

0.91

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