chr2-227263852-G-A

Variant names:

• chr2-227263852-G-A
• rs34505188
• NM_000091.5:c.1223G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.1223G>A​(p.Arg408His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,613,942 control chromosomes in the GnomAD database, including 5,700 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R408C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.073 (544 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5156 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.914
• Publications: 30 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0022709966).
• BP6: Variant 2-227263852-G-A is Benign according to our data. Variant chr2-227263852-G-A is described in ClinVar as Benign. ClinVar VariationId is 254977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1223G>A	p.Arg408His	missense_variant	Exon 21 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1223G>A	p.Arg408His	missense_variant	Exon 21 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0725 AC: 11038 AN: 152156 Hom.: 537 Cov.: 32

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0729

Gnomad OTH AF: 0.0829

GnomAD2 exomes AF: 0.0943 AC: 23514 AN: 249242 AF XY: 0.0938

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.0899

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0760

Gnomad OTH exome AF: 0.0999

GnomAD4 exome AF: 0.0789 AC: 115270 AN: 1461668 Hom.: 5156 Cov.: 35 AF XY: 0.0798 AC XY: 58023 AN XY: 727142

African (AFR) AF: 0.0311 AC: 1042 AN: 33476

American (AMR) AF: 0.175 AC: 7811 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0902 AC: 2358 AN: 26134

East Asian (EAS) AF: 0.123 AC: 4864 AN: 39694

South Asian (SAS) AF: 0.112 AC: 9651 AN: 86252

European-Finnish (FIN) AF: 0.0357 AC: 1908 AN: 53396

Middle Eastern (MID) AF: 0.0988 AC: 570 AN: 5768

European-Non Finnish (NFE) AF: 0.0735 AC: 81673 AN: 1111852

Other (OTH) AF: 0.0893 AC: 5393 AN: 60380

GnomAD4 genome AF: 0.0727 AC: 11065 AN: 152274 Hom.: 544 Cov.: 32 AF XY: 0.0734 AC XY: 5467 AN XY: 74466

African (AFR) AF: 0.0329 AC: 1368 AN: 41554

American (AMR) AF: 0.163 AC: 2488 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3468

East Asian (EAS) AF: 0.152 AC: 789 AN: 5186

South Asian (SAS) AF: 0.106 AC: 509 AN: 4824

European-Finnish (FIN) AF: 0.0315 AC: 334 AN: 10614

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0729 AC: 4959 AN: 68010

Other (OTH) AF: 0.0896 AC: 189 AN: 2110

Alfa AF: 0.0750 Hom.: 1422

Bravo AF: 0.0809

TwinsUK AF: 0.0774 AC: 287

ALSPAC AF: 0.0719 AC: 277

ESP6500AA AF: 0.0330 AC: 123

ESP6500EA AF: 0.0770 AC: 630

ExAC AF: 0.0908 AC: 10968

Asia WGS AF: 0.138 AC: 481 AN: 3478

EpiCase AF: 0.0874

EpiControl AF: 0.0900

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Aug 22, 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.

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.Arg408His in exon 21 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 17.54% (2026/11552) of Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs34505188).

Apr 22, 2021

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

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 28% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 26. Only high quality variants are reported.

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alport syndrome Benign:2

Jan 12, 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

Autosomal recessive Alport syndrome Benign:1

Jun 10, 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	0.069
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.95	L
PhyloP100		0.91
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.24
Sift	Benign	0.56	T
Sift4G	Benign	0.13	T
Vest4		0.033
ClinPred		0.019	T
GERP RS		2.1
Varity_R		0.031
gMVP		0.14
Mutation Taster		=94/6	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: rs34505188; hg19: chr2-228128568; COSMIC: COSV99067735; COSMIC: COSV99067735;