rs80109666

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000091.5(COL4A3):c.805G>A(p.Glu269Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,684 control chromosomes in the GnomAD database, including 734 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 164 hom., cov: 32)

Exomes 𝑓: 0.010 ( 570 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.33

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018270016).

BP6

Variant 2-227254151-G-A is Benign according to our data. Variant chr2-227254151-G-A is described in ClinVar as [Benign]. Clinvar id is 255006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227254151-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-227254151-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5 link	c.805G>A	p.Glu269Lys	missense_variant	Exon 14 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.805G>A	p.Glu269Lys	missense_variant	Exon 14 of 52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0293

AC:

4460

AN:

152098

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0672

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.143

Gnomad SAS

AF:

0.0253

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00297

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0232

AC:

5790

AN:

249418

Hom.:

284

AF XY:

0.0214

AC XY:

2894

AN XY:

135310

show subpopulations

Gnomad AFR exome

AF:

0.0694

Gnomad AMR exome

AF:

0.00727

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.153

Gnomad SAS exome

AF:

0.0160

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.00337

Gnomad OTH exome

AF:

0.0182

GnomAD4 exome

AF:

0.00999

AC:

14606

AN:

1461468

Hom.:

570

Cov.:

AF XY:

0.00994

AC XY:

7226

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.0711

Gnomad4 AMR exome

AF:

0.00805

Gnomad4 ASJ exome

AF:

0.0158

Gnomad4 EAS exome

AF:

0.145

Gnomad4 SAS exome

AF:

0.0146

Gnomad4 FIN exome

AF:

0.0251

Gnomad4 NFE exome

AF:

0.00165

Gnomad4 OTH exome

AF:

0.0194

GnomAD4 genome

AF:

0.0293

AC:

4465

AN:

152216

Hom.:

164

Cov.:

AF XY:

0.0306

AC XY:

2276

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0673

Gnomad4 AMR

AF:

0.0152

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.143

Gnomad4 SAS

AF:

0.0249

Gnomad4 FIN

AF:

0.0271

Gnomad4 NFE

AF:

0.00296

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0113

Hom.:

127

Bravo

AF:

0.0312

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.0666

AC:

253

ESP6500EA

AF:

0.00243

AC:

ExAC

AF:

0.0234

AC:

2822

Asia WGS

AF:

0.0960

AC:

332

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00373

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu269Lys in exon 14 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 15.00% (1291/8608) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs80109666). -

Oct 05, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 23, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A3 c.805G>A (p.Glu269Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.023 in 249418 control chromosomes, predominantly at a frequency of 0.15 within the East Asian subpopulation in the gnomAD database, including 220 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 73-folds over the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, autosomal recessive phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.805G>A has been reported in the literature in an individual affected with Alport Syndrome, autosomal recessive, however, authors classify the variant as a polymorphism (Zhang_2012). Four ClinVar submissions (evaluation after 2014) cite the variant three times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Apr 20, 2022

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.019

DANN

Benign

0.70

DEOGEN2

Benign

0.18

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.33

Sift

Benign

0.92

Sift4G

Benign

0.85

Polyphen

0.75

Vest4

0.081

MPC

0.24

ClinPred

0.0082

GERP RS

-5.1

Varity_R

0.048

gMVP

0.43

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