rs16823264

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000092.5(COL4A4):c.17T>C(p.Ile6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,334 control chromosomes in the GnomAD database, including 4,091 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I6V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.093 ( 2111 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 1980 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.00400

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058941543).

BP6

Variant 2-227147467-A-G is Benign according to our data. Variant chr2-227147467-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.17T>C	p.Ile6Thr	missense_variant	Exon 2 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.17T>C	p.Ile6Thr	missense_variant	Exon 2 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes

AF:

0.0924

AC:

14055

AN:

152066

Hom.:

2106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0339

Gnomad ASJ

AF:

0.000578

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0237

AC:

5903

AN:

249444

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.327

Gnomad AMR exome

AF:

0.0153

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.00972

AC:

14202

AN:

1461150

Hom.:

1980

Cov.:

AF XY:

0.00861

AC XY:

6258

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.332

AC:

11013

AN:

33204

American (AMR)

AF:

0.0165

AC:

736

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.00441

AC:

380

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.0220

AC:

127

AN:

5766

European-Non Finnish (NFE)

AF:

0.000592

AC:

658

AN:

1111724

Other (OTH)

AF:

0.0211

AC:

1275

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

559

1117

1676

2234

2793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.0926

AC:

14087

AN:

152184

Hom.:

2111

Cov.:

AF XY:

0.0892

AC XY:

6637

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.321

AC:

13322

AN:

41454

American (AMR)

AF:

0.0338

AC:

516

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000578

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00456

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00135

AC:

AN:

68032

Other (OTH)

AF:

0.0605

AC:

128

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

483

967

1450

1934

2417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0338

Hom.:

2793

Bravo

AF:

0.105

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.317

AC:

1216

ESP6500EA

AF:

0.00133

AC:

ExAC

AF:

0.0286

AC:

3451

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 05, 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.

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

PreventionGenetics, part of Exact Sciences

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.Ile6Thr in exon 2 of COL4A4: This variant is not expected to have clinical sig nificance because it has been identified in 37.44% (495/1322) of African chromos omes by the 1000 Genomes Project (Phase 3; dbSNP rs16823264).

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Alport syndrome

Benign:2

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.

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.49

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.069

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.

PhyloP100

-0.0040

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.33

N;.

REVEL

Benign

0.17

Sift

Benign

0.26

T;.

Sift4G

Uncertain

0.044

D;.

Vest4

0.077

ClinPred

0.0012

GERP RS

-2.4

PromoterAI

0.030

Neutral

(source)

Varity_R

0.043

gMVP

0.33

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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