dbSNP rs288326: FRZB:p.Arg200Trp (chr2-182838608-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001463.4(FRZB):c.598C>T(p.Arg200Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,609,516 control chromosomes in the GnomAD database, including 9,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars).

Frequency

Genomes: 𝑓 0.082 ( 755 hom., cov: 32)

Exomes 𝑓: 0.10 ( 9041 hom. )

Consequence

FRZB
NM_001463.4 missense

Scores

Clinical Significance

Benign; risk factor no assertion criteria provided B:1O:1

Conservation

PhyloP100: 2.31

Publications

79 publications found

Variant links:

Genes affected

FRZB (HGNC:3959): (frizzled related protein) The protein encoded by this gene is a secreted protein that is involved in the regulation of bone development. Defects in this gene are a cause of female-specific osteoarthritis (OA) susceptibility. [provided by RefSeq, Apr 2010]

FRZB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022199154).

BP6

Variant 2-182838608-G-A is Benign according to our data. Variant chr2-182838608-G-A is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 5221.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRZB	NM_001463.4 link	c.598C>T	p.Arg200Trp	missense_variant	Exon 4 of 6	ENST00000295113.5	NP_001454.2	Q92765D9ZGF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRZB	ENST00000295113.5 link	c.598C>T	p.Arg200Trp	missense_variant	Exon 4 of 6	1	NM_001463.4	ENSP00000295113.4		Q92765

Frequencies

GnomAD3 genomes

AF:

0.0818

AC:

12411

AN:

151750

Hom.:

755

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.0847

Gnomad ASJ

AF:

0.161

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0336

Gnomad FIN

AF:

0.0513

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.0886

GnomAD2 exomes

AF:

0.0818

AC:

20449

AN:

249838

AF XY:

0.0840

show subpopulations

Gnomad AFR exome

AF:

0.0272

Gnomad AMR exome

AF:

0.0564

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0520

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.0928

GnomAD4 exome

AF:

0.104

AC:

151565

AN:

1457648

Hom.:

9041

Cov.:

AF XY:

0.103

AC XY:

74509

AN XY:

725312

show subpopulations

African (AFR)

AF:

0.0248

AC:

827

AN:

33368

American (AMR)

AF:

0.0585

AC:

2612

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

4140

AN:

26016

East Asian (EAS)

AF:

0.000176

AC:

AN:

39662

South Asian (SAS)

AF:

0.0392

AC:

3382

AN:

86178

European-Finnish (FIN)

AF:

0.0569

AC:

3035

AN:

53378

Middle Eastern (MID)

AF:

0.0922

AC:

529

AN:

5740

European-Non Finnish (NFE)

AF:

0.118

AC:

131281

AN:

1108472

Other (OTH)

AF:

0.0956

AC:

5752

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

5646

11292

16937

22583

28229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4580

9160

13740

18320

22900

<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:

0.0817

AC:

12405

AN:

151868

Hom.:

755

Cov.:

AF XY:

0.0783

AC XY:

5811

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.0305

AC:

1264

AN:

41440

American (AMR)

AF:

0.0845

AC:

1287

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.161

AC:

558

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0330

AC:

159

AN:

4812

European-Finnish (FIN)

AF:

0.0513

AC:

542

AN:

10568

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8026

AN:

67880

Other (OTH)

AF:

0.0877

AC:

185

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

570

1141

1711

2282

2852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.106

Hom.:

3540

Bravo

AF:

0.0828

TwinsUK

AF:

0.119

AC:

440

ALSPAC

AF:

0.126

AC:

486

ESP6500AA

AF:

0.0338

AC:

149

ESP6500EA

AF:

0.117

AC:

1007

ExAC

AF:

0.0815

AC:

9896

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.124

EpiControl

AF:

0.123

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

FRZB-related disorder

Benign:1

Jun 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Osteoarthritis susceptibility 1

Other:1

Jun 29, 2004

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.42

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

2.3

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.27

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.34

MPC

1.2

ClinPred

0.013

GERP RS

3.2

Varity_R

0.40

gMVP

0.81

Mutation Taster

=84/16

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over