rs1882435

Positions:

Variant summary

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

The NM_000091.5(COL4A3):c.144+12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,560,592 control chromosomes in the GnomAD database, including 68,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6605 hom., cov: 32)

Exomes 𝑓: 0.29 ( 62230 hom. )

Consequence

COL4A3
NM_000091.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.560

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=-0.88).

BP6

Variant 2-227238036-C-A is Benign according to our data. Variant chr2-227238036-C-A is described in ClinVar as [Benign]. Clinvar id is 254981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227238036-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 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.144+12C>A		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.144+12C>A		intron_variant		1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.293

AC:

44436

AN:

151904

Hom.:

6598

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.312

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.428

Gnomad SAS

AF:

0.278

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.301

GnomAD3 exomes

AF:

0.310

AC:

77221

AN:

249472

Hom.:

12394

AF XY:

0.308

AC XY:

41715

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.323

Gnomad EAS exome

AF:

0.458

Gnomad SAS exome

AF:

0.293

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.310

GnomAD4 exome

AF:

0.294

AC:

414371

AN:

1408570

Hom.:

62230

Cov.:

AF XY:

0.295

AC XY:

207388

AN XY:

703904

show subpopulations

Gnomad4 AFR exome

AF:

0.260

Gnomad4 AMR exome

AF:

0.308

Gnomad4 ASJ exome

AF:

0.315

Gnomad4 EAS exome

AF:

0.407

Gnomad4 SAS exome

AF:

0.293

Gnomad4 FIN exome

AF:

0.282

Gnomad4 NFE exome

AF:

0.290

Gnomad4 OTH exome

AF:

0.304

GnomAD4 genome

AF:

0.292

AC:

44462

AN:

152022

Hom.:

6605

Cov.:

AF XY:

0.293

AC XY:

21789

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.261

Gnomad4 AMR

AF:

0.312

Gnomad4 ASJ

AF:

0.310

Gnomad4 EAS

AF:

0.429

Gnomad4 SAS

AF:

0.277

Gnomad4 FIN

AF:

0.275

Gnomad4 NFE

AF:

0.302

Gnomad4 OTH

AF:

0.302

Alfa

AF:

0.307

Hom.:

8375

Bravo

AF:

0.296

Asia WGS

AF:

0.336

AC:

1168

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.144+12C>A in intron 2 of COL4A3: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 45.37% (3907/8612) of East Asian chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1882435) . -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 45% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 42. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal recessive Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Autosomal dominant Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.62

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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