2-227238007-G-C

Variant names:

• chr2-227238007-G-C
• rs13424243
• NM_000091.5:c.127G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8201 hom., cov: 31)
  • Exomes 𝑓: 0.34 (89577 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.14
• Publications: 39 publications found

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]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 254978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.127G>C	p.Gly43Arg	missense_variant	Exon 2 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.127G>C	p.Gly43Arg	missense_variant	Exon 2 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48484 AN: 151848 Hom.: 8194 Cov.: 31

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

GnomAD2 exomes AF: 0.284 AC: 70806 AN: 249520 AF XY: 0.282

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 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.: 28 AF XY: 0.334 AC XY: 241510 AN XY: 723070

African (AFR) AF: 0.311 AC: 10361 AN: 33306

American (AMR) AF: 0.226 AC: 10095 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 8976 AN: 26036

East Asian (EAS) AF: 0.0735 AC: 2911 AN: 39610

South Asian (SAS) AF: 0.144 AC: 12396 AN: 86116

European-Finnish (FIN) AF: 0.331 AC: 17611 AN: 53252

Middle Eastern (MID) AF: 0.280 AC: 1610 AN: 5744

European-Non Finnish (NFE) AF: 0.373 AC: 411686 AN: 1103730

Other (OTH) AF: 0.322 AC: 19323 AN: 60042

GnomAD4 genome AF: 0.319 AC: 48521 AN: 151966 Hom.: 8201 Cov.: 31 AF XY: 0.309 AC XY: 22974 AN XY: 74262

African (AFR) AF: 0.313 AC: 12972 AN: 41422

American (AMR) AF: 0.273 AC: 4169 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1212 AN: 3470

East Asian (EAS) AF: 0.0487 AC: 252 AN: 5170

South Asian (SAS) AF: 0.140 AC: 674 AN: 4806

European-Finnish (FIN) AF: 0.339 AC: 3577 AN: 10552

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.359 AC: 24409 AN: 67980

Other (OTH) AF: 0.319 AC: 672 AN: 2108

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

Submissions by phenotype

not specified Benign:8

Apr 22, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.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). -

May 09, 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 11, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Autosomal recessive Alport syndrome Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Alport syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.8	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.10
MutPred		0.86		Gain of sheet (P = 0.0344);
MPC		0.82
ClinPred		0.048	T
GERP RS		4.3
Varity_R		0.61
gMVP		0.61
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13424243; hg19: chr2-228102723; COSMIC: COSV67415437; COSMIC: COSV67415437;