rs1800517

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000092.5(COL4A4):c.3011C>T(p.Pro1004Leu) variant causes a missense change. The variant allele was found at a frequency of 0.497 in 1,613,426 control chromosomes in the GnomAD database, including 201,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1004P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.51 ( 20139 hom., cov: 31)

Exomes 𝑓: 0.50 ( 180863 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.51

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 -18 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=3.101142E-5).

BP6

Variant 2-227051116-G-A is Benign according to our data. Variant chr2-227051116-G-A is described in ClinVar as [Benign]. Clinvar id is 255028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227051116-G-A is described in Lovd as [Benign]. Variant chr2-227051116-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5 linkuse as main transcript	c.3011C>T	p.Pro1004Leu	missense_variant	33/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5 linkuse as main transcript	c.3011C>T	p.Pro1004Leu	missense_variant	33/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes

AF:

0.513

AC:

77872

AN:

151810

Hom.:

20112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.566

Gnomad AMI

AF:

0.371

Gnomad AMR

AF:

0.514

Gnomad ASJ

AF:

0.556

Gnomad EAS

AF:

0.468

Gnomad SAS

AF:

0.630

Gnomad FIN

AF:

0.499

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.478

Gnomad OTH

AF:

0.500

GnomAD3 exomes

AF:

0.520

AC:

129808

AN:

249542

Hom.:

34169

AF XY:

0.522

AC XY:

70647

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.571

Gnomad AMR exome

AF:

0.552

Gnomad ASJ exome

AF:

0.575

Gnomad EAS exome

AF:

0.453

Gnomad SAS exome

AF:

0.641

Gnomad FIN exome

AF:

0.507

Gnomad NFE exome

AF:

0.480

Gnomad OTH exome

AF:

0.511

GnomAD4 exome

AF:

0.495

AC:

723660

AN:

1461498

Hom.:

180863

Cov.:

AF XY:

0.498

AC XY:

362087

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.566

Gnomad4 AMR exome

AF:

0.549

Gnomad4 ASJ exome

AF:

0.579

Gnomad4 EAS exome

AF:

0.466

Gnomad4 SAS exome

AF:

0.638

Gnomad4 FIN exome

AF:

0.508

Gnomad4 NFE exome

AF:

0.478

Gnomad4 OTH exome

AF:

0.501

GnomAD4 genome

AF:

0.513

AC:

77950

AN:

151928

Hom.:

20139

Cov.:

AF XY:

0.514

AC XY:

38160

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.566

Gnomad4 AMR

AF:

0.514

Gnomad4 ASJ

AF:

0.556

Gnomad4 EAS

AF:

0.468

Gnomad4 SAS

AF:

0.630

Gnomad4 FIN

AF:

0.499

Gnomad4 NFE

AF:

0.478

Gnomad4 OTH

AF:

0.500

Alfa

AF:

0.482

Hom.:

31765

Bravo

AF:

0.515

TwinsUK

AF:

0.483

AC:

1790

ALSPAC

AF:

0.470

AC:

1811

ESP6500AA

AF:

0.582

AC:

2198

ESP6500EA

AF:

0.489

AC:

4022

ExAC

AF:

0.520

AC:

62858

Asia WGS

AF:

0.563

AC:

1959

AN:

3478

EpiCase

AF:

0.462

EpiControl

AF:

0.476

ClinVar

Significance: Benign

Submissions summary: Benign:12

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.Pro1004Leu in exon 33 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 64.34% (10624/16512) of South As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs1800517). -
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 72% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 67. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
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

0.088

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.66

Eigen

Benign

0.024

Eigen_PC

Benign

0.032

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.000031

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

3.1e-9

P;P

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-7.9

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.63

Vest4

0.12

MPC

0.14

ClinPred

0.082

GERP RS

4.6

Varity_R

0.41

gMVP

0.28

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