2-227028004-C-T

Variant names:

• chr2-227028004-C-T
• rs2229813
• NM_000092.5:c.3979G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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. 16/21 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.164
• Publications: 41 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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, 7 uncertain in NM_000092.5
• 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 Benign/Likely_benign. ClinVar VariationId is 191312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.3979G>A	p.Val1327Met	missense_variant	Exon 42 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.3979G>A	p.Val1327Met	missense_variant	Exon 42 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.468 AC: 70889 AN: 151564 Hom.: 16791 Cov.: 30

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

GnomAD2 exomes AF: 0.470 AC: 112717 AN: 239780 AF XY: 0.468

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 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.: 29 AF XY: 0.441 AC XY: 317133 AN XY: 718508

African (AFR) AF: 0.532 AC: 17551 AN: 33020

American (AMR) AF: 0.526 AC: 22996 AN: 43696

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 13337 AN: 25824

East Asian (EAS) AF: 0.403 AC: 15910 AN: 39526

South Asian (SAS) AF: 0.557 AC: 47479 AN: 85232

European-Finnish (FIN) AF: 0.498 AC: 26433 AN: 53052

Middle Eastern (MID) AF: 0.397 AC: 2270 AN: 5716

European-Non Finnish (NFE) AF: 0.421 AC: 462052 AN: 1097830

Other (OTH) AF: 0.442 AC: 26409 AN: 59704

GnomAD4 genome AF: 0.468 AC: 70968 AN: 151682 Hom.: 16825 Cov.: 30 AF XY: 0.469 AC XY: 34755 AN XY: 74096

African (AFR) AF: 0.533 AC: 22057 AN: 41346

American (AMR) AF: 0.470 AC: 7161 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1720 AN: 3464

East Asian (EAS) AF: 0.386 AC: 1983 AN: 5142

South Asian (SAS) AF: 0.550 AC: 2631 AN: 4780

European-Finnish (FIN) AF: 0.494 AC: 5176 AN: 10482

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28846 AN: 67908

Other (OTH) AF: 0.431 AC: 907 AN: 2102

Alfa AF: 0.447 Hom.: 32942

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:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive Alport syndrome Benign:3

May 10, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Updated to Likely benign due to high local frequency -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Alport syndrome Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:2

Apr 03, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked Alport syndrome Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.22
DANN	Benign	0.58
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.00028	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.16
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.21
Sift	Benign	0.58	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.14
ClinPred		0.0012	T
GERP RS		1.6
Varity_R		0.045
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229813; hg19: chr2-227892720; COSMIC: COSV61634374;