rs2228556

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000092.5(COL4A4):c.4080G>A(p.Pro1360Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,601,552 control chromosomes in the GnomAD database, including 159,533 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 16859 hom., cov: 31)

Exomes 𝑓: 0.44 ( 142674 hom. )

Consequence

COL4A4
NM_000092.5 splice_region, synonymous

Scores

Splicing: ADA: 0.0001429

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.529

Publications

20 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 2-227027903-C-T is Benign according to our data. Variant chr2-227027903-C-T is described in ClinVar as Benign. ClinVar VariationId is 255036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.529 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.528 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.4080G>A	p.Pro1360Pro	splice_region synonymous	Exon 42 of 48	NP_000083.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.4080G>A	p.Pro1360Pro	splice_region synonymous	Exon 42 of 48	ENSP00000379866.3

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

71052

AN:

151816

Hom.:

16825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.533

Gnomad AMI

AF:

0.403

Gnomad AMR

AF:

0.469

Gnomad ASJ

AF:

0.496

Gnomad EAS

AF:

0.387

Gnomad SAS

AF:

0.546

Gnomad FIN

AF:

0.496

Gnomad MID

AF:

0.417

Gnomad NFE

AF:

0.425

Gnomad OTH

AF:

0.439

GnomAD2 exomes

AF:

0.472

AC:

117495

AN:

248986

AF XY:

0.469

show subpopulations

Gnomad AFR exome

AF:

0.540

Gnomad AMR exome

AF:

0.534

Gnomad ASJ exome

AF:

0.510

Gnomad EAS exome

AF:

0.398

Gnomad FIN exome

AF:

0.499

Gnomad NFE exome

AF:

0.426

Gnomad OTH exome

AF:

0.455

GnomAD4 exome

AF:

0.440

AC:

637409

AN:

1449618

Hom.:

142674

Cov.:

AF XY:

0.441

AC XY:

318677

AN XY:

721854

show subpopulations

African (AFR)

AF:

0.531

AC:

17597

AN:

33120

American (AMR)

AF:

0.529

AC:

23599

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.516

AC:

13444

AN:

26034

East Asian (EAS)

AF:

0.403

AC:

15961

AN:

39622

South Asian (SAS)

AF:

0.553

AC:

47463

AN:

85898

European-Finnish (FIN)

AF:

0.499

AC:

26626

AN:

53368

Middle Eastern (MID)

AF:

0.397

AC:

2284

AN:

5746

European-Non Finnish (NFE)

AF:

0.421

AC:

463903

AN:

1101214

Other (OTH)

AF:

0.442

AC:

26532

AN:

59966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

16282

32564

48846

65128

81410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14294

28588

42882

57176

71470

<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:

0.468

AC:

71131

AN:

151934

Hom.:

16859

Cov.:

AF XY:

0.470

AC XY:

34866

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.534

AC:

22119

AN:

41434

American (AMR)

AF:

0.470

AC:

7173

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

1719

AN:

3468

East Asian (EAS)

AF:

0.387

AC:

1999

AN:

5160

South Asian (SAS)

AF:

0.546

AC:

2630

AN:

4818

European-Finnish (FIN)

AF:

0.496

AC:

5213

AN:

10518

Middle Eastern (MID)

AF:

0.408

AC:

119

AN:

292

European-Non Finnish (NFE)

AF:

0.425

AC:

28882

AN:

67958

Other (OTH)

AF:

0.433

AC:

911

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1911

3822

5732

7643

9554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<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:

0.437

Hom.:

22782

Bravo

AF:

0.470

Asia WGS

AF:

0.475

AC:

1656

AN:

3478

EpiCase

AF:

0.403

EpiControl

AF:

0.411

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Alport syndrome (2)

Autosomal recessive Alport syndrome (1)

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.41

PhyloP100

0.53

Mutation Taster

=69/31

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.026

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over