rs2229814

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.1444C>T(p.Pro482Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,610,152 control chromosomes in the GnomAD database, including 212,777 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20000 hom., cov: 29)

Exomes 𝑓: 0.51 ( 192777 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.668

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=6.3470297E-6).

BP6

Variant 2-227089883-G-A is Benign according to our data. Variant chr2-227089883-G-A is described in ClinVar as [Benign]. Clinvar id is 255014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227089883-G-A is described in Lovd as [Benign]. Variant chr2-227089883-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.605 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.1444C>T	p.Pro482Ser	missense_variant	21/48	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.1444C>T	p.Pro482Ser	missense_variant	21/48	5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.513

AC:

77589

AN:

151114

Hom.:

19978

Cov.:

show subpopulations

Gnomad AFR

AF:

0.504

Gnomad AMI

AF:

0.498

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.528

Gnomad EAS

AF:

0.498

Gnomad SAS

AF:

0.624

Gnomad FIN

AF:

0.522

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.496

Gnomad OTH

AF:

0.501

GnomAD3 exomes

AF:

0.540

AC:

134535

AN:

249218

Hom.:

37133

AF XY:

0.538

AC XY:

72729

AN XY:

135214

show subpopulations

Gnomad AFR exome

AF:

0.508

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.548

Gnomad EAS exome

AF:

0.487

Gnomad SAS exome

AF:

0.631

Gnomad FIN exome

AF:

0.530

Gnomad NFE exome

AF:

0.491

Gnomad OTH exome

AF:

0.521

GnomAD4 exome

AF:

0.511

AC:

745448

AN:

1458914

Hom.:

192777

Cov.:

AF XY:

0.513

AC XY:

372545

AN XY:

725928

show subpopulations

Gnomad4 AFR exome

AF:

0.506

Gnomad4 AMR exome

AF:

0.656

Gnomad4 ASJ exome

AF:

0.553

Gnomad4 EAS exome

AF:

0.507

Gnomad4 SAS exome

AF:

0.630

Gnomad4 FIN exome

AF:

0.531

Gnomad4 NFE exome

AF:

0.494

Gnomad4 OTH exome

AF:

0.509

GnomAD4 genome

AF:

0.514

AC:

77667

AN:

151238

Hom.:

20000

Cov.:

AF XY:

0.516

AC XY:

38123

AN XY:

73820

show subpopulations

Gnomad4 AFR

AF:

0.504

Gnomad4 AMR

AF:

0.582

Gnomad4 ASJ

AF:

0.528

Gnomad4 EAS

AF:

0.498

Gnomad4 SAS

AF:

0.624

Gnomad4 FIN

AF:

0.522

Gnomad4 NFE

AF:

0.496

Gnomad4 OTH

AF:

0.502

Alfa

AF:

0.501

Hom.:

30521

Bravo

AF:

0.517

TwinsUK

AF:

0.498

AC:

1845

ALSPAC

AF:

0.481

AC:

1853

ESP6500AA

AF:

0.525

AC:

1967

ESP6500EA

AF:

0.502

AC:

4115

ExAC

AF:

0.534

AC:

64523

EpiCase

AF:

0.476

EpiControl

AF:

0.486

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro482Ser in exon 21 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 68.08% (7860/11546) of Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs2229814). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	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 73% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 68. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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, 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. -
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

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.34

DEOGEN2

Benign

0.072

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0000063

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.030

REVEL

Benign

0.25

Sift

Benign

0.75

Sift4G

Benign

0.74

Polyphen

0.0

Vest4

0.019

MPC

0.14

ClinPred

0.000018

GERP RS

0.34

Varity_R

0.028

gMVP

0.047

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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