rs56247709

chr2-227059421-T-Achr2-227059421-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000092.5(COL4A4):c.2367A>T(p.Gly789=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,614,062 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G789G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0084 (72 hom.)
• Consequence: COL4A4 NM_000092.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.798

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-227059421-T-A is Benign according to our data. Variant chr2-227059421-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 334721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227059421-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.798 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00565 (861/152258) while in subpopulation NFE AF= 0.00973 (662/68006). AF 95% confidence interval is 0.00912. There are 4 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.2367A>T	p.Gly789=	synonymous_variant	28/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.2367A>T	p.Gly789=	synonymous_variant	28/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 860 AN: 152140 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00973

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00571 AC: 1426 AN: 249570 Hom.: 9 AF XY: 0.00569 AC XY: 771 AN XY: 135404

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00428

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00995

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00845 AC: 12345 AN: 1461804 Hom.: 72 Cov.: 32 AF XY: 0.00845 AC XY: 6145 AN XY: 727206

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00499

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.00565 AC: 861 AN: 152258 Hom.: 4 Cov.: 31 AF XY: 0.00544 AC XY: 405 AN XY: 74454

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00686

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00973

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00519 Hom.: 1

Bravo AF: 0.00539

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gly789Gly in exon 28 of COL4A4: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 0.93% (622/66730) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs56247709). -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COL4A4: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	This variant is associated with the following publications: (PMID: 17396119, 20029656) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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.	Nov 01, 2019	- -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.4
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs56247709; hg19: chr2-227924137; COSMIC: COSV61636217;