rs35998949

Positions:

Variant summary

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

The NM_000092.5(COL4A4):c.1781A>G(p.Glu594Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,614,088 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 112 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 119 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.42

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029699206).

BP6

Variant 2-227080465-T-C is Benign according to our data. Variant chr2-227080465-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 218426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227080465-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0698 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.1781A>G	p.Glu594Gly	missense_variant	24/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 linkuse as main transcript	c.1781A>G	p.Glu594Gly	missense_variant	24/48	5	NM_000092.5	ENSP00000379866	P1

Frequencies

GnomAD3 genomes

AF:

0.0209

AC:

3181

AN:

152102

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0719

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.0168

GnomAD3 exomes

AF:

0.00521

AC:

1301

AN:

249558

Hom.:

AF XY:

0.00402

AC XY:

544

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.0732

Gnomad AMR exome

AF:

0.00342

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000300

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00215

AC:

3137

AN:

1461868

Hom.:

119

Cov.:

AF XY:

0.00187

AC XY:

1361

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0733

Gnomad4 AMR exome

AF:

0.00356

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000215

Gnomad4 OTH exome

AF:

0.00434

GnomAD4 genome

AF:

0.0210

AC:

3193

AN:

152220

Hom.:

112

Cov.:

AF XY:

0.0204

AC XY:

1521

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0720

Gnomad4 AMR

AF:

0.00981

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.00289

Hom.:

Bravo

AF:

0.0247

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0745

AC:

277

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00635

AC:

767

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Glu594Gly in exon 24 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 7.24% (709/9798) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs35998949). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely 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 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2019

- -

Autosomal recessive Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.67

MutationAssessor

Benign

2.0

MutationTaster

Benign

0.97

N;N

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.10

Sift

Benign

0.43

Sift4G

Benign

0.41

Polyphen

0.0030

Vest4

0.24

MVP

0.58

MPC

0.50

ClinPred

0.022

GERP RS

2.0

Varity_R

0.094

gMVP

0.60

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