chr2-227051208-T-C

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.2969-50A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 1,593,442 control chromosomes in the GnomAD database, including 7,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 539 hom., cov: 32)

Exomes 𝑓: 0.094 ( 6669 hom. )

Consequence

COL4A4
NM_000092.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.894

Publications

14 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 (BayesDel_noAF=-0.9).

BP6

Variant 2-227051208-T-C is Benign according to our data. Variant chr2-227051208-T-C is described in ClinVar as Benign. ClinVar VariationId is 682773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.2969-50A>G		intron_variant	Intron 32 of 47	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.2969-50A>G		intron_variant	Intron 32 of 47	5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.0798

AC:

12127

AN:

152062

Hom.:

537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0482

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0732

Gnomad ASJ

AF:

0.0851

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.0621

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0917

Gnomad OTH

AF:

0.0880

GnomAD2 exomes

AF:

0.0906

AC:

22490

AN:

248274

AF XY:

0.0944

show subpopulations

Gnomad AFR exome

AF:

0.0442

Gnomad AMR exome

AF:

0.0515

Gnomad ASJ exome

AF:

0.0878

Gnomad EAS exome

AF:

0.167

Gnomad FIN exome

AF:

0.0636

Gnomad NFE exome

AF:

0.0914

Gnomad OTH exome

AF:

0.0950

GnomAD4 exome

AF:

0.0936

AC:

134950

AN:

1441262

Hom.:

6669

Cov.:

AF XY:

0.0950

AC XY:

68267

AN XY:

718308

show subpopulations

African (AFR)

AF:

0.0469

AC:

1550

AN:

33052

American (AMR)

AF:

0.0530

AC:

2369

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0841

AC:

2184

AN:

25958

East Asian (EAS)

AF:

0.175

AC:

6947

AN:

39604

South Asian (SAS)

AF:

0.125

AC:

10726

AN:

85796

European-Finnish (FIN)

AF:

0.0651

AC:

3474

AN:

53330

Middle Eastern (MID)

AF:

0.129

AC:

737

AN:

5734

European-Non Finnish (NFE)

AF:

0.0926

AC:

101268

AN:

1093378

Other (OTH)

AF:

0.0954

AC:

5695

AN:

59716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

6313

12626

18939

25252

31565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3786

7572

11358

15144

18930

<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:

0.0798

AC:

12140

AN:

152180

Hom.:

539

Cov.:

AF XY:

0.0796

AC XY:

5922

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0482

AC:

2001

AN:

41518

American (AMR)

AF:

0.0730

AC:

1116

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0851

AC:

295

AN:

3468

East Asian (EAS)

AF:

0.182

AC:

940

AN:

5154

South Asian (SAS)

AF:

0.134

AC:

644

AN:

4816

European-Finnish (FIN)

AF:

0.0621

AC:

659

AN:

10604

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0917

AC:

6234

AN:

68012

Other (OTH)

AF:

0.0932

AC:

197

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

599

1198

1796

2395

2994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<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:

0.0885

Hom.:

2573

Bravo

AF:

0.0773

Asia WGS

AF:

0.154

AC:

533

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

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. -

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

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.73

(source)

DANN

Benign

0.50

PhyloP100

-0.89

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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