rs1800519

chr2-227054742-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000092.5(COL4A4):c.2717-5A>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001587
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: -0.296

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]

ACMG classification

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 GnomAd at 21 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.2717-5A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.2717-5A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1784 AN: 152174 Hom.: 21 Cov.: 33

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.: 30 AF XY: 0.0119 AC XY: 1606 AN XY: 134508

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.: 31 AF XY: 0.0151 AC XY: 10942 AN XY: 726896

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.: 21 Cov.: 33 AF XY: 0.0112 AC XY: 833 AN XY: 74464

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.: 7

Bravo AF: 0.0122

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0225

EpiControl AF: 0.0226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	COL4A4: BP4, BS1, BS2 -
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	-	- -

not specified Benign:2

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

Alport syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 29, 2019	- -
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. -

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;C4746547: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

Other links and lift over

dbSNP: rs1800519; hg19: chr2-227919458;