chr2-227308920-A-G

Variant names:

• chr2-227308920-A-G
• rs77964815
• NM_000091.5:c.4484A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000091.5(COL4A3):​c.4484A>G​(p.Gln1495Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00915 in 1,614,128 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (79 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.14
• Publications: 15 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=0.00907886).
• BP6: Variant 2-227308920-A-G is Benign according to our data. Variant chr2-227308920-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00564 (859/152386) while in subpopulation NFE AF = 0.0103 (700/68046). AF 95% confidence interval is 0.00966. There are 3 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	NM_000091.5	MANE Select	c.4484A>G	p.Gln1495Arg	missense	Exon 49 of 52	NP_000082.2
	MFF-DT	NR_102371.1		n.48-3265T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.4484A>G	p.Gln1495Arg	missense	Exon 49 of 52	ENSP00000379823.3
	MFF-DT	ENST00000439598.6	TSL:1	n.48-3265T>C		intron	N/A
	COL4A3	ENST00000469504.2	TSL:1	n.434-284A>G		intron	N/A	ENSP00000493493.1

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 858 AN: 152268 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00629 AC: 1569 AN: 249324 AF XY: 0.00664

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00205

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00952 AC: 13913 AN: 1461742 Hom.: 79 Cov.: 32 AF XY: 0.00926 AC XY: 6736 AN XY: 727174

African (AFR) AF: 0.00176 AC: 59 AN: 33476

American (AMR) AF: 0.00192 AC: 86 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00531 AC: 458 AN: 86256

European-Finnish (FIN) AF: 0.00289 AC: 154 AN: 53314

Middle Eastern (MID) AF: 0.00816 AC: 47 AN: 5762

European-Non Finnish (NFE) AF: 0.0114 AC: 12707 AN: 1111984

Other (OTH) AF: 0.00641 AC: 387 AN: 60392

GnomAD4 genome AF: 0.00564 AC: 859 AN: 152386 Hom.: 3 Cov.: 33 AF XY: 0.00464 AC XY: 346 AN XY: 74514

African (AFR) AF: 0.00166 AC: 69 AN: 41594

American (AMR) AF: 0.00222 AC: 34 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4832

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 700 AN: 68046

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00852 Hom.: 12

Bravo AF: 0.00562

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00235 AC: 9

ESP6500EA AF: 0.00956 AC: 79

ExAC AF: 0.00676 AC: 817

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.00925

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Jan 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17216251, 19525337, 14582039, 30661074, 12028435, 14871398, 30467950)

Jan 30, 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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL4A3: BS1, BS2

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:5

May 27, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 18, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 30, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A3 c.4484A>G (p.Gln1495Arg) results in a conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0063 in 249324 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive phenotype (0.0019), strongly suggesting that the variant is benign. At-least one publication reports c.4484A>G with incomplete segregation, variable penetrance and non-informative phenotypes ranging from type-I diabetes, focal segmental glomerulosclerosis, microscopic hematuria, with normal renal function, normal hearing and no ocular abnormalities among in individuals in a family reportedly diagnosed with Alport Syndrome (Choi_2019). Furthermore, the variant did not segregate in an autosomal recessive manner in this family and the authors suggest a possible digenic association of this variant with another variant in the COL4A5 gene. No conclusions can be drawn from these data and this report does not provide unequivocal evidence supporting an association of this variant with Alport syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=2). None of the submitters has cited the report utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gln1495Arg in exon 49 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 1.01% (671/66718) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs77964815).

Kidney disorder Benign:1

Apr 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alport syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Benign:1

Apr 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.79
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.099
Eigen_PC	Benign	0.069
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	-0.020	T
MutationAssessor	Benign	0.95	L
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.49	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.66	P
Vest4		0.26
MVP		0.80
MPC		0.20
ClinPred		0.049	T
GERP RS		6.0
Varity_R		0.23
gMVP		0.63
Mutation Taster		=53/47	polymorphism

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: rs77964815; hg19: chr2-228173636; COSMIC: COSV99067741; COSMIC: COSV99067741;