rs1800516

Positions:

chr2-227082177-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000092.5(COL4A4):c.1634G>C(p.Gly545Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0318 in 1,613,770 control chromosomes in the GnomAD database, including 899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 84 hom., cov: 32)

Exomes 𝑓: 0.032 ( 815 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.08

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:

COL4A4 (HGNC:):

COL4A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072841644).

BP6

Variant 2-227082177-C-G is Benign according to our data. Variant chr2-227082177-C-G is described in ClinVar as [Benign]. Clinvar id is 255015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227082177-C-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5 linkuse as main transcript	c.1634G>C	p.Gly545Ala	missense_variant	23/48	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 linkuse as main transcript	c.1634G>C	p.Gly545Ala	missense_variant	23/48	5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.0308

AC:

4679

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0342

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0264

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0343

Gnomad OTH

AF:

0.0344

GnomAD3 exomes

AF:

0.0272

AC:

6788

AN:

249500

Hom.:

122

AF XY:

0.0271

AC XY:

3665

AN XY:

135358

show subpopulations

Gnomad AFR exome

AF:

0.0323

Gnomad AMR exome

AF:

0.0189

Gnomad ASJ exome

AF:

0.0431

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00788

Gnomad FIN exome

AF:

0.0226

Gnomad NFE exome

AF:

0.0375

Gnomad OTH exome

AF:

0.0370

GnomAD4 exome

AF:

0.0319

AC:

46619

AN:

1461516

Hom.:

815

Cov.:

AF XY:

0.0316

AC XY:

22982

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0359

Gnomad4 AMR exome

AF:

0.0196

Gnomad4 ASJ exome

AF:

0.0414

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00822

Gnomad4 FIN exome

AF:

0.0215

Gnomad4 NFE exome

AF:

0.0352

Gnomad4 OTH exome

AF:

0.0333

GnomAD4 genome

AF:

0.0307

AC:

4678

AN:

152254

Hom.:

Cov.:

AF XY:

0.0295

AC XY:

2198

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0342

Gnomad4 AMR

AF:

0.0263

Gnomad4 ASJ

AF:

0.0435

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00891

Gnomad4 FIN

AF:

0.0213

Gnomad4 NFE

AF:

0.0343

Gnomad4 OTH

AF:

0.0341

Alfa

AF:

0.0344

Hom.:

Bravo

AF:

0.0315

TwinsUK

AF:

0.0410

AC:

152

ALSPAC

AF:

0.0319

AC:

123

ESP6500AA

AF:

0.0322

AC:

125

ESP6500EA

AF:

0.0358

AC:

296

ExAC

AF:

0.0282

AC:

3408

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0359

EpiControl

AF:

0.0407

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gly545Ala in exon 23 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 3.93% (2622/66738) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs1800516). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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	Eurofins Ntd Llc (ga)	Feb 13, 2018	- -

not provided

Benign:2

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

Alport syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0073

MetaSVM

Uncertain

0.31

MutationAssessor

Pathogenic

3.9

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.32

MPC

0.64

ClinPred

0.085

GERP RS

5.3

Varity_R

0.85

gMVP

0.99

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