rs13027659

Positions:

chr2-227051131-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 5.80

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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=7}. 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 GnomAd4 at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.2996G>A	p.Gly999Glu	missense_variant	33/48	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.2996G>A	p.Gly999Glu	missense_variant	33/48	5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1908

AN:

152148

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0120

AC XY:

1628

AN XY:

135382

show subpopulations

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.:

AF XY:

0.0168

AC XY:

12253

AN XY:

727226

show subpopulations

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.:

Cov.:

AF XY:

0.0117

AC XY:

871

AN XY:

74442

show subpopulations

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.:

Bravo

AF:

0.0123

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.00212

AC:

ESP6500EA

AF:

0.0157

AC:

129

ExAC

AF:

0.0117

AC:

1417

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0213

EpiControl

AF:

0.0200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

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	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	COL4A4: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	GeneDx	May 17, 2018	This variant is associated with the following publications: (PMID: 12631110, 27884173, 30467950) -

Alport syndrome

Uncertain:1Benign: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, no assertion criteria provided

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

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.029

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.3

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MPC

0.18

ClinPred

0.087

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

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