rs13027659

chr2-227051131-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000092.5(COL4A4):c.2996G>A(p.Gly999Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0166 in 1,614,116 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 32)
  • Exomes 𝑓: 0.017 (280 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 5.80

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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.029466987).
• BP6: Variant 2-227051131-C-T is Benign according to our data. Variant chr2-227051131-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255027.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=8}. Variant chr2-227051131-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-227051131-C-T is described in Lovd as [Likely_benign]. Variant chr2-227051131-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1908/152266) while in subpopulation NFE AF= 0.0213 (1446/68028). AF 95% confidence interval is 0.0203. There are 18 homozygotes in gnomad4. There are 871 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.2996G>A	p.Gly999Glu	missense_variant	33/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.2996G>A	p.Gly999Glu	missense_variant	33/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1908 AN: 152148 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00981

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.0116 AC: 2895 AN: 249534 Hom.: 27 AF XY: 0.0120 AC XY: 1628 AN XY: 135382

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00782

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00932

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0171 AC: 24929 AN: 1461850 Hom.: 280 Cov.: 34 AF XY: 0.0168 AC XY: 12253 AN XY: 727226

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00814

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00400

Gnomad4 FIN exome AF: 0.00966

Gnomad4 NFE exome AF: 0.0204

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0125 AC: 1908 AN: 152266 Hom.: 18 Cov.: 32 AF XY: 0.0117 AC XY: 871 AN XY: 74442

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00981

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0179 Hom.: 38

Bravo AF: 0.0123

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00212 AC: 8

ESP6500EA AF: 0.0157 AC: 129

ExAC AF: 0.0117 AC: 1417

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	COL4A4: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2018	This variant is associated with the following publications: (PMID: 12631110, 27884173, 30467950) -

Alport syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 20, 2018

p.Gly999Glu in exon 33 of COL4A4: This variant is not expected to have clinical signficance because it has been identified in 1.9% (2548/12662) of European chro mosomes, including 27 homozygote individuals, by the the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs13027659). ACMG/AMP Cri teria applied: PP3; BA1. -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 07, 2022

- -

COL4A4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.029	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MPC		0.18
ClinPred		0.087	T
GERP RS		5.5
Varity_R		0.94
gMVP		0.95

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: rs13027659; hg19: chr2-227915847; COSMIC: COSV61631385;