chr2-227028004-C-T

Position:

chr2-227028004-C-T

Variant summary

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

The NM_000092.5(COL4A4):c.3979G>A(p.Val1327Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,595,282 control chromosomes in the GnomAD database, including 158,911 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 16825 hom., cov: 30)

Exomes 𝑓: 0.44 ( 142086 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.164

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=2.7811527E-4).

BP6

Variant 2-227028004-C-T is Benign according to our data. Variant chr2-227028004-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 191312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227028004-C-T is described in Lovd as [Benign]. Variant chr2-227028004-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.533 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.3979G>A	p.Val1327Met	missense_variant	42/48	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.3979G>A	p.Val1327Met	missense_variant	42/48	5	NM_000092.5	ENSP00000379866	P1

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

70889

AN:

151564

Hom.:

16791

Cov.:

show subpopulations

Gnomad AFR

AF:

0.533

Gnomad AMI

AF:

0.404

Gnomad AMR

AF:

0.469

Gnomad ASJ

AF:

0.497

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.551

Gnomad FIN

AF:

0.494

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.425

Gnomad OTH

AF:

0.437

GnomAD3 exomes

AF:

0.470

AC:

112717

AN:

239780

Hom.:

26841

AF XY:

0.468

AC XY:

60944

AN XY:

130238

show subpopulations

Gnomad AFR exome

AF:

0.537

Gnomad AMR exome

AF:

0.531

Gnomad ASJ exome

AF:

0.510

Gnomad EAS exome

AF:

0.396

Gnomad SAS exome

AF:

0.556

Gnomad FIN exome

AF:

0.496

Gnomad NFE exome

AF:

0.423

Gnomad OTH exome

AF:

0.453

GnomAD4 exome

AF:

0.439

AC:

634437

AN:

1443600

Hom.:

142086

Cov.:

AF XY:

0.441

AC XY:

317133

AN XY:

718508

show subpopulations

Gnomad4 AFR exome

AF:

0.532

Gnomad4 AMR exome

AF:

0.526

Gnomad4 ASJ exome

AF:

0.516

Gnomad4 EAS exome

AF:

0.403

Gnomad4 SAS exome

AF:

0.557

Gnomad4 FIN exome

AF:

0.498

Gnomad4 NFE exome

AF:

0.421

Gnomad4 OTH exome

AF:

0.442

GnomAD4 genome

AF:

0.468

AC:

70968

AN:

151682

Hom.:

16825

Cov.:

AF XY:

0.469

AC XY:

34755

AN XY:

74096

show subpopulations

Gnomad4 AFR

AF:

0.533

Gnomad4 AMR

AF:

0.470

Gnomad4 ASJ

AF:

0.497

Gnomad4 EAS

AF:

0.386

Gnomad4 SAS

AF:

0.550

Gnomad4 FIN

AF:

0.494

Gnomad4 NFE

AF:

0.425

Gnomad4 OTH

AF:

0.431

Alfa

AF:

0.435

Hom.:

15791

Bravo

AF:

0.470

TwinsUK

AF:

0.424

AC:

1571

ALSPAC

AF:

0.418

AC:

1611

ESP6500AA

AF:

0.528

AC:

1935

ESP6500EA

AF:

0.422

AC:

3442

ExAC

AF:

0.461

AC:

55664

Asia WGS

AF:

0.479

AC:

1668

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Feb 02, 2016	p.Val1327Met in exon 42 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 45% (26293/58266) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs2229813). -
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 62% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 58. Only high quality variants are reported. -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive Alport syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	Population allele frequency is 47% (rs2229813, 125,895/267,302 alleles in gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -
Likely benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 10, 2024	Updated to Likely benign due to high local frequency -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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 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. -

X-linked Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.22

DANN

Benign

0.58

DEOGEN2

Benign

0.23

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.22

MetaRNN

Benign

0.00028

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.31

PROVEAN

Benign

2.0

REVEL

Benign

0.21

Sift

Benign

0.58

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.043

MPC

0.14

ClinPred

0.0012

GERP RS

1.6

Varity_R

0.045

gMVP

0.12

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