rs1800519

Positions:

chr2-227054742-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000092.5(COL4A4):c.2717-5A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,524 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 21 hom., cov: 33)

Exomes 𝑓: 0.015 ( 227 hom. )

Consequence

COL4A4
NM_000092.5 splice_region, intron

Scores

Splicing: ADA: 0.00001587

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: -0.296

Variant links:

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 links:

COL4A4 (HGNC:):

COL4A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1785/152292) while in subpopulation NFE AF= 0.0191 (1302/68028). AF 95% confidence interval is 0.0183. There are 21 homozygotes in gnomad4. There are 833 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5 linkuse as main transcript	c.2717-5A>T		splice_region_variant, intron_variant		ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 linkuse as main transcript	c.2717-5A>T		splice_region_variant, intron_variant		5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1784

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0114

AC:

2818

AN:

247698

Hom.:

AF XY:

0.0119

AC XY:

1606

AN XY:

134508

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0120

Gnomad EAS exome

AF:

0.000168

Gnomad SAS exome

AF:

0.00350

Gnomad FIN exome

AF:

0.00307

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.0152

AC:

22177

AN:

1461232

Hom.:

227

Cov.:

AF XY:

0.0151

AC XY:

10942

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.00425

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.0132

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00357

Gnomad4 FIN exome

AF:

0.00290

Gnomad4 NFE exome

AF:

0.0177

Gnomad4 OTH exome

AF:

0.0149

GnomAD4 genome

AF:

0.0117

AC:

1785

AN:

152292

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

833

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00282

Gnomad4 AMR

AF:

0.0156

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.0191

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0170

Hom.:

Bravo

AF:

0.0122

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0225

EpiControl

AF:

0.0226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL4A4: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	This variant is associated with the following publications: (PMID: 15618242) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Alport syndrome

Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 29, 2019	- -

Autosomal recessive Alport syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Medical Genetics, University of Parma

Mar 11, 2020

- -

Benign familial hematuria;C5882663:Autosomal dominant Alport syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Medical Genetics, University of Parma

Mar 11, 2020

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.15

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000016

dbscSNV1_RF

Benign

0.0

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