chr2-227256084-T-C

Position:

chr2-227256084-T-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.933+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,612,948 control chromosomes in the GnomAD database, including 868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 54 hom., cov: 33)

Exomes 𝑓: 0.032 ( 814 hom. )

Consequence

COL4A3
NM_000091.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0190

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=-0.83).

BP6

Variant 2-227256084-T-C is Benign according to our data. Variant chr2-227256084-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227256084-T-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0507 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.933+14T>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.933+14T>C		intron_variant		1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

3678

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0246

Gnomad ASJ

AF:

0.0694

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0228

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0336

Gnomad OTH

AF:

0.0411

GnomAD3 exomes

AF:

0.0270

AC:

6739

AN:

249404

Hom.:

136

AF XY:

0.0286

AC XY:

3873

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.00794

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.0719

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0282

Gnomad FIN exome

AF:

0.0189

Gnomad NFE exome

AF:

0.0330

Gnomad OTH exome

AF:

0.0345

GnomAD4 exome

AF:

0.0316

AC:

46118

AN:

1460620

Hom.:

814

Cov.:

AF XY:

0.0318

AC XY:

23107

AN XY:

726718

show subpopulations

Gnomad4 AFR exome

AF:

0.00711

Gnomad4 AMR exome

AF:

0.0198

Gnomad4 ASJ exome

AF:

0.0737

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0290

Gnomad4 FIN exome

AF:

0.0187

Gnomad4 NFE exome

AF:

0.0337

Gnomad4 OTH exome

AF:

0.0308

GnomAD4 genome

AF:

0.0241

AC:

3678

AN:

152328

Hom.:

Cov.:

AF XY:

0.0240

AC XY:

1784

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00810

Gnomad4 AMR

AF:

0.0246

Gnomad4 ASJ

AF:

0.0694

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0228

Gnomad4 FIN

AF:

0.0183

Gnomad4 NFE

AF:

0.0336

Gnomad4 OTH

AF:

0.0407

Alfa

AF:

0.0330

Hom.:

Bravo

AF:

0.0238

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.933+14T>C in intron 16 of COL4A3: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence an d has been identified in 3.58% (2388/66624) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55928538) . -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.3

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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