rs150979437

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000092.5(COL4A4):c.2630G>A(p.Arg877Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,613,816 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R877W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 8 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 0.0520

Publications

11 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 -11 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000092.5

BP4

Computational evidence support a benign effect (MetaRNN=0.005477667).

BP6

Variant 2-227056031-C-T is Benign according to our data. Variant chr2-227056031-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255023.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00302 (459/152076) while in subpopulation EAS AF = 0.0231 (119/5152). AF 95% confidence interval is 0.0197. There are 6 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD,SD gene

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.2630G>A	p.Arg877Gln	missense	Exon 30 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.2630G>A	p.Arg877Gln	missense	Exon 30 of 48	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.0234

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.00768

GnomAD2 exomes

AF:

0.00383

AC:

956

AN:

249316

AF XY:

0.00377

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.0207

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.00362

Gnomad OTH exome

AF:

0.00380

GnomAD4 exome

AF:

0.00276

AC:

4037

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00275

AC XY:

1999

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00168

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00536

AC:

140

AN:

26136

East Asian (EAS)

AF:

0.0111

AC:

441

AN:

39698

South Asian (SAS)

AF:

0.000719

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00266

AC:

2958

AN:

1111922

Other (OTH)

AF:

0.00354

AC:

214

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

258

516

773

1031

1289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00302

AC:

459

AN:

152076

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41482

American (AMR)

AF:

0.00392

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3466

East Asian (EAS)

AF:

0.0231

AC:

119

AN:

5152

South Asian (SAS)

AF:

0.000623

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00208

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00291

AC:

198

AN:

67972

Other (OTH)

AF:

0.00760

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00288

Hom.:

Bravo

AF:

0.00308

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00109

AC:

ESP6500EA

AF:

0.00331

AC:

ExAC

AF:

0.00416

AC:

502

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (5)

Alport syndrome (2)

Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

0.38

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.072

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

PhyloP100

0.052

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.32

REVEL

Benign

0.18

Sift

Benign

0.43

Sift4G

Benign

0.31

Polyphen

0.0070

Vest4

0.21

MVP

0.34

MPC

0.16

ClinPred

0.00097

GERP RS

-1.9

Varity_R

0.021

gMVP

0.057

Mutation Taster

=100/0

polymorphism

(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