rs77964815

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000091.5(COL4A3):c.4484A>G(p.Gln1495Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00915 in 1,614,128 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 79 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.14

Publications

15 publications found

Variant links:

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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. [provided by RefSeq, Jun 2010]

COL4A3 links:

MFF-DT (HGNC:41067): (MFF divergent transcript)

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00907886).

BP6

Variant 2-227308920-A-G is Benign according to our data. Variant chr2-227308920-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00564 (859/152386) while in subpopulation NFE AF = 0.0103 (700/68046). AF 95% confidence interval is 0.00966. There are 3 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. 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
	COL4A3	NM_000091.5	MANE Select	c.4484A>G	p.Gln1495Arg	missense	Exon 49 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.48-3265T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.4484A>G	p.Gln1495Arg	missense	Exon 49 of 52	ENSP00000379823.3	Q01955-1
MFF-DT	ENST00000439598.6	TSL:1	n.48-3265T>C		intron	N/A
COL4A3	ENST00000469504.2	TSL:1	n.434-284A>G		intron	N/A	ENSP00000493493.1	A0A2R8Y2F0

Frequencies

GnomAD3 genomes

AF:

0.00563

AC:

858

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00629

AC:

1569

AN:

249324

AF XY:

0.00664

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00205

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.00479

GnomAD4 exome

AF:

0.00952

AC:

13913

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00926

AC XY:

6736

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

33476

American (AMR)

AF:

0.00192

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00531

AC:

458

AN:

86256

European-Finnish (FIN)

AF:

0.00289

AC:

154

AN:

53314

Middle Eastern (MID)

AF:

0.00816

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0114

AC:

12707

AN:

1111984

Other (OTH)

AF:

0.00641

AC:

387

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

720

1440

2159

2879

3599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.00564

AC:

859

AN:

152386

Hom.:

Cov.:

AF XY:

0.00464

AC XY:

346

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41594

American (AMR)

AF:

0.00222

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00476

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0103

AC:

700

AN:

68046

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00852

Hom.:

Bravo

AF:

0.00562

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00235

AC:

ESP6500EA

AF:

0.00956

AC:

ExAC

AF:

0.00676

AC:

817

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00971

EpiControl

AF:

0.00925

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (6)

Alport syndrome (1)

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome (1)

Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.19

Eigen

Benign

-0.099

Eigen_PC

Benign

0.069

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0091

MetaSVM

Uncertain

-0.020

MutationAssessor

Benign

0.95

PhyloP100

2.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.49

REVEL

Uncertain

0.31

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.66

Vest4

0.26

MVP

0.80

MPC

0.20

ClinPred

0.049

GERP RS

6.0

Varity_R

0.23

gMVP

0.63

Mutation Taster

=53/47

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