rs61735304

Variant names:

Variant summary

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

The NM_012193.4(FZD4):c.97C>T(p.Pro33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,612,504 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 18 hom., cov: 32)

Exomes 𝑓: 0.018 ( 304 hom. )

Consequence

FZD4
NM_012193.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.09

Publications

28 publications found

Variant links:

COSMIC-nc: COSV107540119

Genes affected

FZD4 (HGNC:4042): (frizzled class receptor 4) This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the Wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. This protein may play a role as a positive regulator of the Wingless type MMTV integration site signaling pathway. A transcript variant retaining intronic sequence and encoding a shorter isoform has been described, however, its expression is not supported by other experimental evidence. [provided by RefSeq, Jul 2008]

FZD4 Gene-Disease associations (from GenCC):

exudative vitreoretinopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
exudative vitreoretinopathy 1
Inheritance: SD, Unknown, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
persistent hyperplastic primary vitreous
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FZD4 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=0.01789704).

BP6

Variant 11-86954989-G-A is Benign according to our data. Variant chr11-86954989-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0126 (1913/152190) while in subpopulation AMR AF = 0.0215 (329/15298). AF 95% confidence interval is 0.0196. There are 18 homozygotes in GnomAd4. There are 910 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1913 SD,AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD4	NM_012193.4 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 2	ENST00000531380.2	NP_036325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 2	1	NM_012193.4	ENSP00000434034.1

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1909

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0203

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0169

AC:

4093

AN:

242758

AF XY:

0.0155

show subpopulations

Gnomad AFR exome

AF:

0.00337

Gnomad AMR exome

AF:

0.0467

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0179

AC:

26069

AN:

1460314

Hom.:

304

Cov.:

AF XY:

0.0173

AC XY:

12569

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.00296

AC:

AN:

33470

American (AMR)

AF:

0.0427

AC:

1910

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

369

AN:

26112

East Asian (EAS)

AF:

0.000101

AC:

AN:

39694

South Asian (SAS)

AF:

0.0137

AC:

1179

AN:

86240

European-Finnish (FIN)

AF:

0.00256

AC:

134

AN:

52410

Middle Eastern (MID)

AF:

0.00573

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0193

AC:

21436

AN:

1111676

Other (OTH)

AF:

0.0150

AC:

905

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1334

2669

4003

5338

6672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

860

1720

2580

3440

4300

<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:

0.0126

AC:

1913

AN:

152190

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

910

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00455

AC:

189

AN:

41564

American (AMR)

AF:

0.0215

AC:

329

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5142

South Asian (SAS)

AF:

0.0199

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0173

AC:

1176

AN:

67958

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0170

Hom.:

Bravo

AF:

0.0142

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00252

AC:

ESP6500EA

AF:

0.0162

AC:

139

ExAC

AF:

0.0145

AC:

1759

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21179236, 28982955, 24744206, 27535533, 15733276, 15223780, 22995991) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FZD4: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Exudative vitreoretinopathy 1

Benign:3

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Pro33Ser variant in FZD4 has been identified in an individual with exudative vitreoretinopathy (PMID: 15733276), but has been identified in >4% of Latino chromosomes and 39 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant exudative vitreoretinopathy. -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 150/12934=1.15% -

Oct 28, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.26

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.57

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

2.1

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.69

REVEL

Benign

0.17

Sift

Benign

0.41

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.046

MPC

0.28

ClinPred

0.0088

GERP RS

3.3

PromoterAI

0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.45

Mutation Taster

=95/5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over