chr2-227266453-A-G

Position:

chr2-227266453-A-G

Variant summary

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

The NM_000091.5(COL4A3):c.1352A>G(p.His451Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0802 in 1,613,644 control chromosomes in the GnomAD database, including 5,881 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.083 ( 627 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5254 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0730

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055891275).

BP6

Variant 2-227266453-A-G is Benign according to our data. Variant chr2-227266453-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 254979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227266453-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.1352A>G	p.His451Arg	missense_variant	22/52	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.1352A>G	p.His451Arg	missense_variant	22/52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0831

AC:

12636

AN:

152130

Hom.:

620

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0685

Gnomad AMI

AF:

0.0582

Gnomad AMR

AF:

0.168

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0311

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0732

Gnomad OTH

AF:

0.0936

GnomAD3 exomes

AF:

0.0969

AC:

24153

AN:

249370

Hom.:

1431

AF XY:

0.0958

AC XY:

12960

AN XY:

135296

show subpopulations

Gnomad AFR exome

AF:

0.0693

Gnomad AMR exome

AF:

0.178

Gnomad ASJ exome

AF:

0.0900

Gnomad EAS exome

AF:

0.153

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0761

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.0799

AC:

116781

AN:

1461396

Hom.:

5254

Cov.:

AF XY:

0.0807

AC XY:

58703

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.0671

Gnomad4 AMR exome

AF:

0.177

Gnomad4 ASJ exome

AF:

0.0902

Gnomad4 EAS exome

AF:

0.123

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0357

Gnomad4 NFE exome

AF:

0.0735

Gnomad4 OTH exome

AF:

0.0923

GnomAD4 genome

AF:

0.0832

AC:

12664

AN:

152248

Hom.:

627

Cov.:

AF XY:

0.0837

AC XY:

6229

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0685

Gnomad4 AMR

AF:

0.168

Gnomad4 ASJ

AF:

0.100

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.106

Gnomad4 FIN

AF:

0.0311

Gnomad4 NFE

AF:

0.0731

Gnomad4 OTH

AF:

0.100

Alfa

AF:

0.0848

Hom.:

1461

Bravo

AF:

0.0931

TwinsUK

AF:

0.0769

AC:

285

ALSPAC

AF:

0.0719

AC:

277

ESP6500AA

AF:

0.0665

AC:

245

ESP6500EA

AF:

0.0767

AC:

628

ExAC

AF:

0.0938

AC:

11330

Asia WGS

AF:

0.140

AC:

487

AN:

3478

EpiCase

AF:

0.0875

EpiControl

AF:

0.0899

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.His451Arg in exon 22 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 17.79% (2042/11476) of Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs11677877). -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 24. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 11, 2017	- -

Alport syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal recessive Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.048

DANN

Benign

0.49

DEOGEN2

Benign

0.39

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.063

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.66

MutationAssessor

Benign

-0.21

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.45

REVEL

Benign

0.21

Sift

Benign

0.62

Sift4G

Benign

0.59

Polyphen

0.14

Vest4

0.0090

MPC

0.25

ClinPred

0.00055

GERP RS

-4.1

Varity_R

0.041

gMVP

0.12

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