rs2228555

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.4548A>G(p.Val1516Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 1,613,658 control chromosomes in the GnomAD database, including 229,696 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. V1516V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.58 ( 26184 hom., cov: 34)

Exomes 𝑓: 0.52 ( 203512 hom. )

Consequence

COL4A4
NM_000092.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.31

Publications

30 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 2-227008279-T-C is Benign according to our data. Variant chr2-227008279-T-C is described in ClinVar as Benign. ClinVar VariationId is 255041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.72 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.4548A>G	p.Val1516Val	synonymous	Exon 47 of 48	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.4548A>G	p.Val1516Val	synonymous	Exon 47 of 48	ENSP00000379866.3	P53420
	COL4A4	ENST00000682098.1		c.190-40A>G		intron	N/A	ENSP00000508331.1	A0A804HLF6

Frequencies

GnomAD3 genomes

AF:

0.578

AC:

87919

AN:

152048

Hom.:

26138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.727

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.543

Gnomad ASJ

AF:

0.532

Gnomad EAS

AF:

0.569

Gnomad SAS

AF:

0.674

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.502

Gnomad OTH

AF:

0.543

GnomAD2 exomes

AF:

0.557

AC:

138571

AN:

248564

AF XY:

0.556

show subpopulations

Gnomad AFR exome

AF:

0.734

Gnomad AMR exome

AF:

0.581

Gnomad ASJ exome

AF:

0.547

Gnomad EAS exome

AF:

0.557

Gnomad FIN exome

AF:

0.544

Gnomad NFE exome

AF:

0.499

Gnomad OTH exome

AF:

0.534

GnomAD4 exome

AF:

0.524

AC:

766451

AN:

1461492

Hom.:

203512

Cov.:

AF XY:

0.527

AC XY:

383127

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.734

AC:

24555

AN:

33476

American (AMR)

AF:

0.578

AC:

25834

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.548

AC:

14331

AN:

26130

East Asian (EAS)

AF:

0.576

AC:

22883

AN:

39694

South Asian (SAS)

AF:

0.672

AC:

57985

AN:

86238

European-Finnish (FIN)

AF:

0.545

AC:

29120

AN:

53408

Middle Eastern (MID)

AF:

0.496

AC:

2860

AN:

5768

European-Non Finnish (NFE)

AF:

0.501

AC:

556667

AN:

1111704

Other (OTH)

AF:

0.534

AC:

32216

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

20709

41418

62126

82835

103544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16424

32848

49272

65696

82120

<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:

0.578

AC:

88023

AN:

152166

Hom.:

26184

Cov.:

AF XY:

0.578

AC XY:

42966

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.727

AC:

30198

AN:

41528

American (AMR)

AF:

0.544

AC:

8313

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.532

AC:

1847

AN:

3472

East Asian (EAS)

AF:

0.569

AC:

2945

AN:

5176

South Asian (SAS)

AF:

0.674

AC:

3253

AN:

4828

European-Finnish (FIN)

AF:

0.536

AC:

5668

AN:

10578

Middle Eastern (MID)

AF:

0.510

AC:

150

AN:

294

European-Non Finnish (NFE)

AF:

0.502

AC:

34143

AN:

67980

Other (OTH)

AF:

0.542

AC:

1144

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1922

3844

5765

7687

9609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

750

1500

2250

3000

3750

<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:

0.537

Hom.:

56389

Bravo

AF:

0.584

Asia WGS

AF:

0.639

AC:

2222

AN:

3478

EpiCase

AF:

0.480

EpiControl

AF:

0.492

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (3)

Alport syndrome (2)

Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.9

(source)

DANN

Benign

0.67

PhyloP100

-1.3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over