rs2229812

Positions:

• chr2-227032170-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000092.5(COL4A4):​c.3684G>A​(p.Lys1228Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,613,548 control chromosomes in the GnomAD database, including 161,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16881 hom., cov: 33)
  • Exomes 𝑓: 0.44 (144735 hom.)
• Consequence: COL4A4 NM_000092.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.447

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-227032170-C-T is Benign according to our data. Variant chr2-227032170-C-T is described in ClinVar as [Benign]. Clinvar id is 255032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227032170-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.447 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.3684G>A	p.Lys1228Lys	synonymous_variant	39/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.3684G>A	p.Lys1228Lys	synonymous_variant	39/48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71072 AN: 152016 Hom.: 16850 Cov.: 33

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.413

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.436

GnomAD3 exomes AF: 0.474 AC: 118173 AN: 249372 Hom.: 28526 AF XY: 0.472 AC XY: 63870 AN XY: 135290

Gnomad AFR exome AF: 0.536

Gnomad AMR exome AF: 0.534

Gnomad ASJ exome AF: 0.514

Gnomad EAS exome AF: 0.400

Gnomad SAS exome AF: 0.568

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.442 AC: 645697 AN: 1461414 Hom.: 144735 Cov.: 55 AF XY: 0.444 AC XY: 322713 AN XY: 727026

Gnomad4 AFR exome AF: 0.529

Gnomad4 AMR exome AF: 0.528

Gnomad4 ASJ exome AF: 0.522

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.569

Gnomad4 FIN exome AF: 0.499

Gnomad4 NFE exome AF: 0.423

Gnomad4 OTH exome AF: 0.445

GnomAD4 genome AF: 0.468 AC: 71147 AN: 152134 Hom.: 16881 Cov.: 33 AF XY: 0.469 AC XY: 34895 AN XY: 74354

Gnomad4 AFR AF: 0.531

Gnomad4 AMR AF: 0.469

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.388

Gnomad4 SAS AF: 0.565

Gnomad4 FIN AF: 0.493

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.430

Alfa AF: 0.451 Hom.: 8464

Bravo AF: 0.469

Asia WGS AF: 0.482 AC: 1679 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.410

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 67% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 62. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Lys1228Lys in exon 39 of COL4A4: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 57.17% (9433/1650 0) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs2229812). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alport syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.37
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2229812; hg19: chr2-227896886; COSMIC: COSV61632591;