chr2-227056031-C-T

Position:

chr2-227056031-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000092.5(COL4A4):c.2630G>A(p.Arg877Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,613,816 control chromosomes in the GnomAD database, including 14 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R877W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 8 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 0.0520

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 -11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000092.5

BP4

Computational evidence support a benign effect (MetaRNN=0.005477667).

BP6

Variant 2-227056031-C-T is Benign according to our data. Variant chr2-227056031-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255023.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=8}. Variant chr2-227056031-C-T is described in Lovd as [Benign]. Variant chr2-227056031-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00302 (459/152076) while in subpopulation EAS AF= 0.0231 (119/5152). AF 95% confidence interval is 0.0197. There are 6 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5 linkuse as main transcript	c.2630G>A	p.Arg877Gln	missense_variant	30/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5 linkuse as main transcript	c.2630G>A	p.Arg877Gln	missense_variant	30/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.0234

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.00768

GnomAD3 exomes

AF:

0.00383

AC:

956

AN:

249316

Hom.:

AF XY:

0.00377

AC XY:

510

AN XY:

135336

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.0207

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.00362

Gnomad OTH exome

AF:

0.00380

GnomAD4 exome

AF:

0.00276

AC:

4037

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00275

AC XY:

1999

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.00536

Gnomad4 EAS exome

AF:

0.0111

Gnomad4 SAS exome

AF:

0.000719

Gnomad4 FIN exome

AF:

0.00170

Gnomad4 NFE exome

AF:

0.00266

Gnomad4 OTH exome

AF:

0.00354

GnomAD4 genome

AF:

0.00302

AC:

459

AN:

152076

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.0231

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00208

Gnomad4 NFE

AF:

0.00291

Gnomad4 OTH

AF:

0.00760

Alfa

AF:

0.00288

Hom.:

Bravo

AF:

0.00308

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00109

AC:

ESP6500EA

AF:

0.00331

AC:

ExAC

AF:

0.00416

AC:

502

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2018	- -
Likely 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	Aug 20, 2019	This variant is associated with the following publications: (PMID: 17216251, 30819905, 29098738, 12028435, 31180159) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 11, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COL4A4: BP4, BS1, BS2 -

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Arg877Gln in exon 30 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 2.43% (208/8574) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs150979437). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2024	- -

Alport syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 06, 2019	- -
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. -

Autosomal recessive Alport syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Medical Genetics, University of Parma

Mar 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

0.38

DANN

Benign

0.64

DEOGEN2

Benign

0.072

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.32

REVEL

Benign

0.18

Sift

Benign

0.43

Sift4G

Benign

0.31

Polyphen

0.0070

Vest4

0.21

MVP

0.34

MPC

0.16

ClinPred

0.00097

GERP RS

-1.9

Varity_R

0.021

gMVP

0.057

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