rs77431913

Positions:

chr2-227254099-G-A

Variant summary

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

The NM_000091.5(COL4A3):c.766-13G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,612,466 control chromosomes in the GnomAD database, including 915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 197 hom., cov: 32)

Exomes 𝑓: 0.010 ( 718 hom. )

Consequence

COL4A3
NM_000091.5 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.120

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-227254099-G-A is Benign according to our data. Variant chr2-227254099-G-A is described in ClinVar as [Benign]. Clinvar id is 255005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227254099-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 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.766-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1 linkuse as main transcript	n.1592+5079C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.766-13G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000091.5	ENSP00000379823	P1	Q01955-1
MFF-DT	ENST00000439598.6 linkuse as main transcript	n.1592+5079C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4624

AN:

152082

Hom.:

196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0685

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.0267

Gnomad FIN

AF:

0.0270

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.0249

AC:

6207

AN:

249190

Hom.:

361

AF XY:

0.0229

AC XY:

3100

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.0703

Gnomad AMR exome

AF:

0.00733

Gnomad ASJ exome

AF:

0.00408

Gnomad EAS exome

AF:

0.181

Gnomad SAS exome

AF:

0.0165

Gnomad FIN exome

AF:

0.0277

Gnomad NFE exome

AF:

0.00320

Gnomad OTH exome

AF:

0.0185

GnomAD4 exome

AF:

0.0105

AC:

15287

AN:

1460266

Hom.:

718

Cov.:

AF XY:

0.0104

AC XY:

7565

AN XY:

726550

show subpopulations

Gnomad4 AFR exome

AF:

0.0709

Gnomad4 AMR exome

AF:

0.00796

Gnomad4 ASJ exome

AF:

0.00475

Gnomad4 EAS exome

AF:

0.168

Gnomad4 SAS exome

AF:

0.0154

Gnomad4 FIN exome

AF:

0.0252

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.0203

GnomAD4 genome

AF:

0.0304

AC:

4627

AN:

152200

Hom.:

197

Cov.:

AF XY:

0.0318

AC XY:

2365

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0685

Gnomad4 AMR

AF:

0.0147

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.170

Gnomad4 SAS

AF:

0.0261

Gnomad4 FIN

AF:

0.0270

Gnomad4 NFE

AF:

0.00290

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.0322

Asia WGS

AF:

0.103

AC:

358

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.766-13G>A in intron 13 of COL4A3: This variant is not expected to have clinica l significance because it has been identified in 18.09% (1554/8590) of East Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs77431913). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Alport syndrome

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

2.9

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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