rs77964815

Positions:

chr2-227308920-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

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. 13/20 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.14

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:):

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A3_HUMAN there are 24 pathogenic changes around while only 2 benign (92%) in NM_000091.5

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 [Likely_benign]. Clinvar id is 254998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227308920-A-G is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.4484A>G	p.Gln1495Arg	missense_variant	49/52	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.4484A>G	p.Gln1495Arg	missense_variant	49/52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.00563

AC:

858

AN:

152268

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00629

AC:

1569

AN:

249324

Hom.:

AF XY:

0.00664

AC XY:

898

AN XY:

135286

show subpopulations

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 SAS exome

AF:

0.00477

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.:

Cov.:

AF XY:

0.00926

AC XY:

6736

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00176

Gnomad4 AMR exome

AF:

0.00192

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00531

Gnomad4 FIN exome

AF:

0.00289

Gnomad4 NFE exome

AF:

0.0114

Gnomad4 OTH exome

AF:

0.00641

GnomAD4 genome

AF:

0.00564

AC:

859

AN:

152386

Hom.:

Cov.:

AF XY:

0.00464

AC XY:

346

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00476

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.0103

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00910

Hom.:

Bravo

AF:

0.00562

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00235

AC:

ESP6500EA

AF:

0.00956

AC:

ExAC

AF:

0.00676

AC:

817

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00971

EpiControl

AF:

0.00925

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COL4A3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2019	This variant is associated with the following publications: (PMID: 17216251, 19525337, 14582039, 30661074, 12028435, 14871398, 30467950) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2021	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. -

Kidney disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.099

Eigen_PC

Benign

0.069

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0091

T;T

MetaSVM

Uncertain

-0.020

MutationAssessor

Benign

0.95

L;.

PrimateAI

Uncertain

0.53

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

GERP RS

6.0

Varity_R

0.23

gMVP

0.63

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