rs56243460

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000091.5(COL4A3):c.1576-15T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,611,610 control chromosomes in the GnomAD database, including 1,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.061 ( 399 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1380 hom. )

Consequence

COL4A3
NM_000091.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.08

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:41067): (MFF divergent transcript)

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-227270755-T-G is Benign according to our data. Variant chr2-227270755-T-G is described in ClinVar as [Benign]. Clinvar id is 254984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5 link	c.1576-15T>G		intron_variant	Intron 24 of 51	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 link	c.1576-15T>G		intron_variant	Intron 24 of 51	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0606

AC:

9212

AN:

152128

Hom.:

400

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0534

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0363

Gnomad OTH

AF:

0.0497

GnomAD3 exomes

AF:

0.0460

AC:

11456

AN:

249188

Hom.:

411

AF XY:

0.0424

AC XY:

5740

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.0771

Gnomad ASJ exome

AF:

0.0212

Gnomad EAS exome

AF:

0.00251

Gnomad SAS exome

AF:

0.0178

Gnomad FIN exome

AF:

0.0986

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0374

GnomAD4 exome

AF:

0.0376

AC:

54827

AN:

1459364

Hom.:

1380

Cov.:

AF XY:

0.0365

AC XY:

26541

AN XY:

726230

show subpopulations

Gnomad4 AFR exome

AF:

0.106

Gnomad4 AMR exome

AF:

0.0743

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.00144

Gnomad4 SAS exome

AF:

0.0184

Gnomad4 FIN exome

AF:

0.0927

Gnomad4 NFE exome

AF:

0.0347

Gnomad4 OTH exome

AF:

0.0376

GnomAD4 genome

AF:

0.0605

AC:

9217

AN:

152246

Hom.:

399

Cov.:

AF XY:

0.0624

AC XY:

4648

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.0535

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.0162

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.0363

Gnomad4 OTH

AF:

0.0491

Alfa

AF:

0.0405

Hom.:

Bravo

AF:

0.0591

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1576-15T>G in intron 24 of COL4A3: This variant is not expected to have clinic al significance because it has been identified in 10.86% (1054/9706) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs56243460). -

Autosomal recessive Alport syndrome

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: 15

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