rs267606745

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000091.5(COL4A3):c.3499G>A(p.Gly1167Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,613,458 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.99

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:41067): (MFF divergent transcript)

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 2-227295044-G-A is Pathogenic according to our data. Variant chr2-227295044-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227295044-G-A is described in Lovd as [Pathogenic]. Variant chr2-227295044-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5 link	c.3499G>A	p.Gly1167Arg	missense_variant	Exon 40 of 52	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 link	c.3499G>A	p.Gly1167Arg	missense_variant	Exon 40 of 52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249476

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alport syndrome

Pathogenic:2

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2024

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_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Alport syndrome, MONDO:0018965, COL4A3-related. 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 and dominant disease, Alport syndrome 3B (MIM#620536) and Alport syndrome 3A (MIM#104200), respectively (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0254 - This variant is suspected mosaic. (I) 0304 - Variant is present in gnomAD <0.01 (v4: 14 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 Gly-X-Y motif in the collagen triple helical domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple families/individuals with Alport syndrome, with autosomal dominant and recessive inheritance having been described (ClinVar, LOVD, PMIDs: 11134255, 32703181, 28542346, 27281700, 14582039). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Jan 26, 2025

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 1167 of the COL4A3 protein (p.Gly1167Arg). This variant is present in population databases (rs267606745, gnomAD 0.004%). This missense change has been observed in individuals with Alport syndrome or familial hematuria (PMID: 11134255, 14582039, 27281700, 28542346; internal data). ClinVar contains an entry for this variant (Variation ID: 17492). 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 COL4A3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hematuria, benign familial, 2;C5882663:Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive

Pathogenic:1

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive Alport syndrome

Pathogenic:1

Mar 19, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Alport syndrome

Pathogenic:1

Jan 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

1.0

Gain of methylation at G1167 (P = 0.0308);

MVP

0.95

MPC

0.23

ClinPred

1.0

GERP RS

5.8

Varity_R

0.96

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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