2-227266453-A-G

Variant names:

• chr2-227266453-A-G
• rs11677877
• NM_000091.5:c.1352A>G

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.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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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. H451P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.083 (627 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5254 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0730
• Publications: 40 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000091.5
• 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 Benign/Likely_benign. ClinVar VariationId is 254979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1352A>G	p.His451Arg	missense_variant	Exon 22 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1352A>G	p.His451Arg	missense_variant	Exon 22 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0831 AC: 12636 AN: 152130 Hom.: 620 Cov.: 32

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

GnomAD2 exomes AF: 0.0969 AC: 24153 AN: 249370 AF XY: 0.0958

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 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.: 31 AF XY: 0.0807 AC XY: 58703 AN XY: 727044

African (AFR) AF: 0.0671 AC: 2248 AN: 33478

American (AMR) AF: 0.177 AC: 7905 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0902 AC: 2356 AN: 26128

East Asian (EAS) AF: 0.123 AC: 4862 AN: 39682

South Asian (SAS) AF: 0.112 AC: 9649 AN: 86246

European-Finnish (FIN) AF: 0.0357 AC: 1909 AN: 53404

Middle Eastern (MID) AF: 0.101 AC: 581 AN: 5768

European-Non Finnish (NFE) AF: 0.0735 AC: 81700 AN: 1111612

Other (OTH) AF: 0.0923 AC: 5571 AN: 60374

GnomAD4 genome AF: 0.0832 AC: 12664 AN: 152248 Hom.: 627 Cov.: 32 AF XY: 0.0837 AC XY: 6229 AN XY: 74444

African (AFR) AF: 0.0685 AC: 2846 AN: 41538

American (AMR) AF: 0.168 AC: 2570 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 347 AN: 3466

East Asian (EAS) AF: 0.152 AC: 788 AN: 5188

South Asian (SAS) AF: 0.106 AC: 512 AN: 4828

European-Finnish (FIN) AF: 0.0311 AC: 330 AN: 10616

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0731 AC: 4975 AN: 68014

Other (OTH) AF: 0.100 AC: 212 AN: 2116

Alfa AF: 0.0828 Hom.: 2760

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

Submissions by phenotype

not specified Benign:7

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.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). -

Dec 22, 2017

Eurofins Ntd Llc (ga)

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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 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. -

Sep 25, 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. -

not provided Benign:3

Sep 11, 2017

Athena Diagnostics

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Alport syndrome Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal recessive Alport syndrome Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis Benign:1

Sep 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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	0.052
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.048
DANN	Benign	0.49
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.063	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.21	N
PhyloP100		-0.073
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.21
Sift	Benign	0.62	T
Sift4G	Benign	0.59	T
Polyphen		0.14	B
Vest4		0.0090
MPC		0.25
ClinPred		0.00055	T
GERP RS		-4.1
Varity_R		0.041
gMVP		0.12
Mutation Taster		=100/0	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: rs11677877; hg19: chr2-228131169; COSMIC: COSV67414527; COSMIC: COSV67414527;