NM_000092.5:c.3011C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000092.5(COL4A4):c.3011C>T(p.Pro1004Leu) variant causes a missense change. The variant allele was found at a frequency of 0.497 in 1,613,426 control chromosomes in the GnomAD database, including 201,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1004P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.51 ( 20139 hom., cov: 31)

Exomes 𝑓: 0.50 ( 180863 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.51

Publications

46 publications found

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 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

COL4A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

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

BP4

Computational evidence support a benign effect (MetaRNN=3.101142E-5).

BP6

Variant 2-227051116-G-A is Benign according to our data. Variant chr2-227051116-G-A is described in ClinVar as Benign. ClinVar VariationId is 255028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.3011C>T	p.Pro1004Leu	missense_variant	Exon 33 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.3011C>T	p.Pro1004Leu	missense_variant	Exon 33 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes

AF:

0.513

AC:

77872

AN:

151810

Hom.:

20112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.566

Gnomad AMI

AF:

0.371

Gnomad AMR

AF:

0.514

Gnomad ASJ

AF:

0.556

Gnomad EAS

AF:

0.468

Gnomad SAS

AF:

0.630

Gnomad FIN

AF:

0.499

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.478

Gnomad OTH

AF:

0.500

GnomAD2 exomes

AF:

0.520

AC:

129808

AN:

249542

AF XY:

0.522

show subpopulations

Gnomad AFR exome

AF:

0.571

Gnomad AMR exome

AF:

0.552

Gnomad ASJ exome

AF:

0.575

Gnomad EAS exome

AF:

0.453

Gnomad FIN exome

AF:

0.507

Gnomad NFE exome

AF:

0.480

Gnomad OTH exome

AF:

0.511

GnomAD4 exome

AF:

0.495

AC:

723660

AN:

1461498

Hom.:

180863

Cov.:

AF XY:

0.498

AC XY:

362087

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.566

AC:

18955

AN:

33474

American (AMR)

AF:

0.549

AC:

24542

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

15128

AN:

26130

East Asian (EAS)

AF:

0.466

AC:

18504

AN:

39696

South Asian (SAS)

AF:

0.638

AC:

55020

AN:

86252

European-Finnish (FIN)

AF:

0.508

AC:

27148

AN:

53414

Middle Eastern (MID)

AF:

0.510

AC:

2944

AN:

5768

European-Non Finnish (NFE)

AF:

0.478

AC:

531186

AN:

1111650

Other (OTH)

AF:

0.501

AC:

30233

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

21561

43123

64684

86246

107807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15876

31752

47628

63504

79380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.513

AC:

77950

AN:

151928

Hom.:

20139

Cov.:

AF XY:

0.514

AC XY:

38160

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.566

AC:

23470

AN:

41442

American (AMR)

AF:

0.514

AC:

7841

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.556

AC:

1929

AN:

3470

East Asian (EAS)

AF:

0.468

AC:

2410

AN:

5152

South Asian (SAS)

AF:

0.630

AC:

3032

AN:

4812

European-Finnish (FIN)

AF:

0.499

AC:

5256

AN:

10530

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.478

AC:

32477

AN:

67964

Other (OTH)

AF:

0.500

AC:

1051

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1937

3874

5811

7748

9685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.488

Hom.:

70010

Bravo

AF:

0.515

TwinsUK

AF:

0.483

AC:

1790

ALSPAC

AF:

0.470

AC:

1811

ESP6500AA

AF:

0.582

AC:

2198

ESP6500EA

AF:

0.489

AC:

4022

ExAC

AF:

0.520

AC:

62858

Asia WGS

AF:

0.563

AC:

1959

AN:

3478

EpiCase

AF:

0.462

EpiControl

AF:

0.476

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

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.Pro1004Leu in exon 33 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 64.34% (10624/16512) of South As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs1800517). -

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 72% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 67. Only high quality variants are reported. -

not provided

Benign:3

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

- -

Apr 28, 2017

Athena Diagnostics

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

0.088

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.66

Eigen

Benign

0.024

Eigen_PC

Benign

0.032

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.000031

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

PhyloP100

4.5

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-7.9

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.63

Vest4

0.12

MPC

0.14

ClinPred

0.082

GERP RS

4.6

Varity_R

0.41

gMVP

0.28

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over