rs3769641

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000092.5(COL4A4):c.2384-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,613,482 control chromosomes in the GnomAD database, including 6,350 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.076 ( 471 hom., cov: 33)

Exomes 𝑓: 0.087 ( 5879 hom. )

Consequence

COL4A4
NM_000092.5 splice_region, intron

Scores

Splicing: ADA: 0.01959

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.98

Publications

16 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: Orphanet, G2P, Myriad Women’s Health, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Alport syndrome
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
hematuria, benign familial, 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 2-227057605-A-G is Benign according to our data. Variant chr2-227057605-A-G is described in ClinVar as Benign. ClinVar VariationId is 255020.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000092.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	NM_000092.5	MANE Select	c.2384-5T>C		splice_region intron	N/A	NP_000083.3	P53420

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.2384-5T>C		splice_region intron	N/A	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes

AF:

0.0759

AC:

11548

AN:

152148

Hom.:

469

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0709

Gnomad ASJ

AF:

0.0717

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0618

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0847

Gnomad OTH

AF:

0.0837

GnomAD2 exomes

AF:

0.0847

AC:

21109

AN:

249150

AF XY:

0.0880

show subpopulations

Gnomad AFR exome

AF:

0.0456

Gnomad AMR exome

AF:

0.0493

Gnomad ASJ exome

AF:

0.0767

Gnomad EAS exome

AF:

0.168

Gnomad FIN exome

AF:

0.0622

Gnomad NFE exome

AF:

0.0844

Gnomad OTH exome

AF:

0.0884

GnomAD4 exome

AF:

0.0869

AC:

126974

AN:

1461216

Hom.:

5879

Cov.:

AF XY:

0.0881

AC XY:

64054

AN XY:

726898

show subpopulations

African (AFR)

AF:

0.0490

AC:

1641

AN:

33472

American (AMR)

AF:

0.0506

AC:

2262

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0736

AC:

1924

AN:

26134

East Asian (EAS)

AF:

0.175

AC:

6964

AN:

39688

South Asian (SAS)

AF:

0.111

AC:

9581

AN:

86192

European-Finnish (FIN)

AF:

0.0635

AC:

3389

AN:

53390

Middle Eastern (MID)

AF:

0.123

AC:

709

AN:

5768

European-Non Finnish (NFE)

AF:

0.0856

AC:

95163

AN:

1111488

Other (OTH)

AF:

0.0885

AC:

5341

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

5739

11478

17217

22956

28695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3590

7180

10770

14360

17950

<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:

0.0760

AC:

11567

AN:

152266

Hom.:

471

Cov.:

AF XY:

0.0759

AC XY:

5654

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0495

AC:

2057

AN:

41570

American (AMR)

AF:

0.0707

AC:

1082

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0717

AC:

249

AN:

3472

East Asian (EAS)

AF:

0.183

AC:

946

AN:

5166

South Asian (SAS)

AF:

0.119

AC:

576

AN:

4828

European-Finnish (FIN)

AF:

0.0618

AC:

656

AN:

10618

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0847

AC:

5759

AN:

67998

Other (OTH)

AF:

0.0889

AC:

188

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

541

1081

1622

2162

2703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0823

Hom.:

2082

Bravo

AF:

0.0740

Asia WGS

AF:

0.150

AC:

519

AN:

3478

EpiCase

AF:

0.0858

EpiControl

AF:

0.0938

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Alport syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

3.0

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.020

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: -32

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over