chr2-227008067-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2

The NM_000092.5(COL4A4):c.4760C>G(p.Pro1587Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,613,882 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 16 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 0.778

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 -10 ACMG points.

PM1

In a domain Collagen IV NC1 (size 225) in uniprot entity CO4A4_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) in NM_000092.5

BP4

Computational evidence support a benign effect (MetaRNN=0.030847788).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00213 (324/152350) while in subpopulation NFE AF= 0.00367 (250/68032). AF 95% confidence interval is 0.0033. There are 1 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 16 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.4760C>G	p.Pro1587Arg	missense_variant	Exon 47 of 48	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.4760C>G	p.Pro1587Arg	missense_variant	Exon 47 of 48	5	NM_000092.5	ENSP00000379866.3		P53420
COL4A4	ENST00000682098.1 link	c.362C>G	p.Pro121Arg	missense_variant	Exon 2 of 3			ENSP00000508331.1		A0A804HLF6

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

324

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00367

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00203

AC:

504

AN:

248148

Hom.:

AF XY:

0.00207

AC XY:

279

AN XY:

134760

show subpopulations

Gnomad AFR exome

AF:

0.000392

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.000470

Gnomad NFE exome

AF:

0.00338

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.00356

AC:

5201

AN:

1461532

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

2473

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00150

Gnomad4 FIN exome

AF:

0.000433

Gnomad4 NFE exome

AF:

0.00427

Gnomad4 OTH exome

AF:

0.00315

GnomAD4 genome

AF:

0.00213

AC:

324

AN:

152350

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00367

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00278

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000771

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00179

AC:

217

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL4A4: BS2 -

Sep 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28780565, 25575550, 24130771, 29924831, 30467950) -

Feb 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL4A4 p.Pro1587Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was found in 1/11 families with Alport syndrome in the proband and two brothers all affected with haematuria and proteinuria as well as the father who was affected with end-stage renal disease (Mencarelli_2015_PMID: 25575550). This family also carried another variant in COL4A4 (c.1623+5G>T) and a variant in COL4A5 (p.Gly684Val), which the authors suggested may have led to a triallelic form of digenic inheritance of the renal phenotype observed in this family (Mencarelli_2015_PMID: 25575550). The p.P1587R variant was also found in a male proband, age 75, with hereditary nephritis who also had a variant in the COL4A3 gene (Chatterjee_2013_PMID: 24130771). The probandâ€šÃ„Ã´s brother and sister had end stage renal disease related to presumed hereditary nephritis, however they were not tested for the variant (Chatterjee_2013_PMID: 24130771). The variant was also identified in dbSNP (ID: rs190148408), ClinVar (classified as a VUS by Athena Diagnostics), Cosmic (FATHMM prediction of neutral; score=0.42) and LOVD 3.0 (reported as likely pathogenic in 3 patients with Alport Syndrome, and as VUS in 6 patients with Alport Syndrome). The variant was identified in control databases in 575 of 279544 chromosomes (2 homozygous) at a frequency of 0.002057 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 438 of 127990 chromosomes (freq: 0.003422), Other in 16 of 7120 chromosomes (freq: 0.002247), South Asian in 57 of 30568 chromosomes (freq: 0.001865), Ashkenazi Jewish in 19 of 10348 chromosomes (freq: 0.001836), African in 14 of 24012 chromosomes (freq: 0.000583), Latino in 19 of 35320 chromosomes (freq: 0.000538) and European (Finnish) in 12 of 24740 chromosomes (freq: 0.000485); it was not observed in the East Asian populations. The p.Pro1587 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome

Uncertain:2Benign:1

Dec 12, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 03, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Apr 24, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro1587Arg in exon 47 of COL4A4: This variant is classified as likely benign, because although it has been reported in 3 individuals with features of Alport s yndrome (Chatterjee 2013, Mencarelli 2015, Sen 2017), it is present in 0.34% (43 0/126088) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org; dbSNP rs190148408). This allele frequency is too high to cause Alport syndrome or hearing loss due to the COL4A4 gene. ACMG/AMP criteria applied: BS1. -

COL4A4-related disorder

Benign:1

Mar 25, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Benign

0.081

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.22

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.031

MetaSVM

Uncertain

-0.054

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.33

Sift

Benign

0.90

Sift4G

Benign

0.79

Polyphen

0.91

Vest4

0.43

MVP

0.77

MPC

0.15

ClinPred

0.049

GERP RS

5.0

Varity_R

0.33

gMVP

0.30

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