rs55667591

Positions:

chr2-227251131-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000091.5(COL4A3):c.547-9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,606,522 control chromosomes in the GnomAD database, including 1,427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 174 hom., cov: 32)

Exomes 𝑓: 0.022 ( 1253 hom. )

Consequence

COL4A3
NM_000091.5 intron

Scores

Splicing: ADA: 0.00004422

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0470

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 2-227251131-A-C is Benign according to our data. Variant chr2-227251131-A-C is described in ClinVar as [Benign]. Clinvar id is 255003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227251131-A-C is described in Lovd as [Benign]. Variant chr2-227251131-A-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.547-9A>C		intron_variant		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.547-9A>C		intron_variant		1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0264

AC:

4012

AN:

152178

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0945

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.0998

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0178

Gnomad OTH

AF:

0.0206

GnomAD3 exomes

AF:

0.0431

AC:

10748

AN:

249262

Hom.:

843

AF XY:

0.0375

AC XY:

5077

AN XY:

135214

show subpopulations

Gnomad AFR exome

AF:

0.00310

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.00626

Gnomad EAS exome

AF:

0.000278

Gnomad SAS exome

AF:

0.0115

Gnomad FIN exome

AF:

0.0893

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0293

GnomAD4 exome

AF:

0.0217

AC:

31506

AN:

1454226

Hom.:

1253

Cov.:

AF XY:

0.0208

AC XY:

15034

AN XY:

724092

show subpopulations

Gnomad4 AFR exome

AF:

0.00297

Gnomad4 AMR exome

AF:

0.173

Gnomad4 ASJ exome

AF:

0.00583

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.0833

Gnomad4 NFE exome

AF:

0.0153

Gnomad4 OTH exome

AF:

0.0179

GnomAD4 genome

AF:

0.0264

AC:

4024

AN:

152296

Hom.:

174

Cov.:

AF XY:

0.0309

AC XY:

2298

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00414

Gnomad4 AMR

AF:

0.0952

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0118

Gnomad4 FIN

AF:

0.0998

Gnomad4 NFE

AF:

0.0178

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0169

Hom.:

Bravo

AF:

0.0264

Asia WGS

AF:

0.00780

AC:

AN:

3476

EpiCase

AF:

0.0133

EpiControl

AF:

0.0146

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2020	Variant summary: COL4A3 c.547-9A>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.043 in 249262 control chromosomes in the gnomAD database, including 843 homozygotes. The observed variant frequency is approximately 22 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. To our knowledge, no occurrence of c.547-9A>C in individuals affected with Alport Syndrome, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Three 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. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2017	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 17, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alport syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.18

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