2-227238007-G-C

Position:

chr2-227238007-G-C

Variant summary

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

The NM_000091.5(COL4A3):c.127G>C(p.Gly43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,604,472 control chromosomes in the GnomAD database, including 97,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8201 hom., cov: 31)

Exomes 𝑓: 0.34 ( 89577 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.14

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=0.005469084).

BP6

Variant 2-227238007-G-C is Benign according to our data. Variant chr2-227238007-G-C is described in ClinVar as [Benign]. Clinvar id is 254978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227238007-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 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.127G>C	p.Gly43Arg	missense_variant	2/52	ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1 linkuse as main transcript	n.1681+79C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.127G>C	p.Gly43Arg	missense_variant	2/52	1	NM_000091.5	ENSP00000379823	P1	Q01955-1
MFF-DT	ENST00000439598.6 linkuse as main transcript	n.1681+79C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.319

AC:

48484

AN:

151848

Hom.:

8194

Cov.:

show subpopulations

Gnomad AFR

AF:

0.313

Gnomad AMI

AF:

0.549

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.349

Gnomad EAS

AF:

0.0488

Gnomad SAS

AF:

0.140

Gnomad FIN

AF:

0.339

Gnomad MID

AF:

0.274

Gnomad NFE

AF:

0.359

Gnomad OTH

AF:

0.323

GnomAD3 exomes

AF:

0.284

AC:

70806

AN:

249520

Hom.:

11647

AF XY:

0.282

AC XY:

38196

AN XY:

135370

show subpopulations

Gnomad AFR exome

AF:

0.308

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.337

Gnomad EAS exome

AF:

0.0388

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.334

Gnomad NFE exome

AF:

0.362

Gnomad OTH exome

AF:

0.314

GnomAD4 exome

AF:

0.341

AC:

494969

AN:

1452506

Hom.:

89577

Cov.:

AF XY:

0.334

AC XY:

241510

AN XY:

723070

show subpopulations

Gnomad4 AFR exome

AF:

0.311

Gnomad4 AMR exome

AF:

0.226

Gnomad4 ASJ exome

AF:

0.345

Gnomad4 EAS exome

AF:

0.0735

Gnomad4 SAS exome

AF:

0.144

Gnomad4 FIN exome

AF:

0.331

Gnomad4 NFE exome

AF:

0.373

Gnomad4 OTH exome

AF:

0.322

GnomAD4 genome

AF:

0.319

AC:

48521

AN:

151966

Hom.:

8201

Cov.:

AF XY:

0.309

AC XY:

22974

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.313

Gnomad4 AMR

AF:

0.273

Gnomad4 ASJ

AF:

0.349

Gnomad4 EAS

AF:

0.0487

Gnomad4 SAS

AF:

0.140

Gnomad4 FIN

AF:

0.339

Gnomad4 NFE

AF:

0.359

Gnomad4 OTH

AF:

0.319

Alfa

AF:

0.322

Hom.:

5112

Bravo

AF:

0.318

TwinsUK

AF:

0.396

AC:

1469

ALSPAC

AF:

0.378

AC:

1457

ESP6500AA

AF:

0.306

AC:

1134

ESP6500EA

AF:

0.371

AC:

3032

ExAC

AF:

0.288

AC:

34832

Asia WGS

AF:

0.123

AC:

427

AN:

3478

EpiCase

AF:

0.357

EpiControl

AF:

0.363

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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.Gly43Arg in exon 2 of COL4A3: This variant is not expected to have clinical si gnificance because it has been identified in 36.20% (24153/66730) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs13424243). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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, 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	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 31% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 29. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2017	Variant summary: The COL4A3 c.127G>C (p.Gly43Arg) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 34826/120756 control chromosomes (5825 homozygotes) at a frequency of 0.2883997, which is approximately 141 times the estimated maximal expected allele frequency of a pathogenic COL4A3 variant (0.0020412), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases/literature classified this variant as benign. Taken together, this variant is classified as benign. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alport syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Autosomal recessive Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

Autosomal dominant Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.23

Eigen_PC

Benign

-0.025

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.8

MutationAssessor

Pathogenic

4.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.41

Sift

Uncertain

0.013

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.10

MutPred

0.86

Gain of sheet (P = 0.0344);

MPC

0.82

ClinPred

0.048

GERP RS

4.3

Varity_R

0.61

gMVP

0.61

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