rs2228557

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000092.5(COL4A4):c.4932C>T(p.Phe1644Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,613,496 control chromosomes in the GnomAD database, including 156,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 17965 hom., cov: 33)

Exomes 𝑓: 0.43 ( 138410 hom. )

Consequence

COL4A4
NM_000092.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.27

Publications

39 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 2-227007466-G-A is Benign according to our data. Variant chr2-227007466-G-A is described in ClinVar as Benign. ClinVar VariationId is 255043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 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.4932C>T	p.Phe1644Phe	synonymous	Exon 48 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.4932C>T	p.Phe1644Phe	synonymous	Exon 48 of 48	ENSP00000379866.3	P53420
	COL4A4	ENST00000682098.1		c.534C>T	p.Phe178Phe	synonymous	Exon 3 of 3	ENSP00000508331.1	A0A804HLF6

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72718

AN:

151926

Hom.:

17924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.602

Gnomad AMI

AF:

0.383

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.447

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.575

Gnomad FIN

AF:

0.477

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.441

GnomAD2 exomes

AF:

0.467

AC:

116579

AN:

249438

AF XY:

0.465

show subpopulations

Gnomad AFR exome

AF:

0.607

Gnomad AMR exome

AF:

0.530

Gnomad ASJ exome

AF:

0.459

Gnomad EAS exome

AF:

0.394

Gnomad FIN exome

AF:

0.484

Gnomad NFE exome

AF:

0.410

Gnomad OTH exome

AF:

0.442

GnomAD4 exome

AF:

0.431

AC:

629995

AN:

1461452

Hom.:

138410

Cov.:

AF XY:

0.434

AC XY:

315231

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.600

AC:

20091

AN:

33480

American (AMR)

AF:

0.524

AC:

23224

AN:

44356

Ashkenazi Jewish (ASJ)

AF:

0.464

AC:

12132

AN:

26136

East Asian (EAS)

AF:

0.403

AC:

15997

AN:

39700

South Asian (SAS)

AF:

0.578

AC:

49866

AN:

86254

European-Finnish (FIN)

AF:

0.483

AC:

25800

AN:

53406

Middle Eastern (MID)

AF:

0.371

AC:

2138

AN:

5762

European-Non Finnish (NFE)

AF:

0.409

AC:

454473

AN:

1111962

Other (OTH)

AF:

0.435

AC:

26274

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

24784

49568

74353

99137

123921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14242

28484

42726

56968

71210

<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:

0.479

AC:

72807

AN:

152044

Hom.:

17965

Cov.:

AF XY:

0.479

AC XY:

35588

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.603

AC:

24982

AN:

41454

American (AMR)

AF:

0.466

AC:

7125

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.447

AC:

1550

AN:

3468

East Asian (EAS)

AF:

0.386

AC:

1997

AN:

5174

South Asian (SAS)

AF:

0.574

AC:

2770

AN:

4826

European-Finnish (FIN)

AF:

0.477

AC:

5042

AN:

10572

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.411

AC:

27963

AN:

67960

Other (OTH)

AF:

0.435

AC:

918

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1900

3800

5701

7601

9501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

666

1332

1998

2664

3330

<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:

0.432

Hom.:

51446

Bravo

AF:

0.482

Asia WGS

AF:

0.487

AC:

1695

AN:

3478

EpiCase

AF:

0.389

EpiControl

AF:

0.394

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

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

-0.46

CADD

Benign

9.8

(source)

DANN

Benign

0.81

PhyloP100

1.3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over