rs2229814

Variant names:

• chr2-227089883-G-A
• rs2229814
• NM_000092.5:c.1444C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-227089883-G-A
• chr2-227089883-G-C
• chr2-227089883-G-T

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.1444C>T​(p.Pro482Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,610,152 control chromosomes in the GnomAD database, including 212,777 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20000 hom., cov: 29)
  • Exomes 𝑓: 0.51 (192777 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.668
• Publications: 45 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=6.3470297E-6).
• BP6: Variant 2-227089883-G-A is Benign according to our data. Variant chr2-227089883-G-A is described in ClinVar as Benign. ClinVar VariationId is 255014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.1444C>T	p.Pro482Ser	missense_variant	Exon 21 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.1444C>T	p.Pro482Ser	missense_variant	Exon 21 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77589 AN: 151114 Hom.: 19978 Cov.: 29

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.501

GnomAD2 exomes AF: 0.540 AC: 134535 AN: 249218 AF XY: 0.538

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.487

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.521

GnomAD4 exome AF: 0.511 AC: 745448 AN: 1458914 Hom.: 192777 Cov.: 37 AF XY: 0.513 AC XY: 372545 AN XY: 725928

African (AFR) AF: 0.506 AC: 16932 AN: 33434

American (AMR) AF: 0.656 AC: 29296 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 14423 AN: 26102

East Asian (EAS) AF: 0.507 AC: 20123 AN: 39662

South Asian (SAS) AF: 0.630 AC: 54269 AN: 86192

European-Finnish (FIN) AF: 0.531 AC: 28281 AN: 53302

Middle Eastern (MID) AF: 0.514 AC: 2960 AN: 5756

European-Non Finnish (NFE) AF: 0.494 AC: 548472 AN: 1109504

Other (OTH) AF: 0.509 AC: 30692 AN: 60272

GnomAD4 genome AF: 0.514 AC: 77667 AN: 151238 Hom.: 20000 Cov.: 29 AF XY: 0.516 AC XY: 38123 AN XY: 73820

African (AFR) AF: 0.504 AC: 20781 AN: 41218

American (AMR) AF: 0.582 AC: 8831 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1829 AN: 3464

East Asian (EAS) AF: 0.498 AC: 2532 AN: 5082

South Asian (SAS) AF: 0.624 AC: 2980 AN: 4776

European-Finnish (FIN) AF: 0.522 AC: 5434 AN: 10408

Middle Eastern (MID) AF: 0.524 AC: 153 AN: 292

European-Non Finnish (NFE) AF: 0.496 AC: 33625 AN: 67830

Other (OTH) AF: 0.502 AC: 1055 AN: 2102

Alfa AF: 0.504 Hom.: 46249

Bravo AF: 0.517

TwinsUK AF: 0.498 AC: 1845

ALSPAC AF: 0.481 AC: 1853

ESP6500AA AF: 0.525 AC: 1967

ESP6500EA AF: 0.502 AC: 4115

ExAC AF: 0.534 AC: 64523

EpiCase AF: 0.476

EpiControl AF: 0.486

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro482Ser in exon 21 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 68.08% (7860/11546) of Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs2229814). -

-

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

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 73% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 68. 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 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. -

Autosomal recessive Alport syndrome Benign:1

Jul 10, 2021

Genome-Nilou Lab

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	0.063
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.34
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000063	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.67
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.25
Sift	Benign	0.75	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.14
ClinPred		0.000018	T
GERP RS		0.34
Varity_R		0.028
gMVP		0.047
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs2229814; hg19: chr2-227954599; COSMIC: COSV61630186;