11-86954989-G-A

Position:

chr11-86954989-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a signal_peptide (size 35) in uniprot entity FZD4_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_012193.4

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 [Likely_benign]. Clinvar id is 193358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86954989-G-A is described in Lovd as [Benign]. Variant chr11-86954989-G-A is described in Lovd as [Pathogenic]. Variant chr11-86954989-G-A is described in Lovd as [Pathogenic]. Variant chr11-86954989-G-A is described in Lovd as [Likely_pathogenic].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1913 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD4	NM_012193.4 linkuse as main transcript	c.97C>T	p.Pro33Ser	missense_variant	1/2	ENST00000531380.2	NP_036325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2 linkuse as main transcript	c.97C>T	p.Pro33Ser	missense_variant	1/2	1	NM_012193.4	ENSP00000434034	P1

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

GnomAD3 exomes

AF:

0.0169

AC:

4093

AN:

242758

Hom.:

AF XY:

0.0155

AC XY:

2066

AN XY:

132932

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 SAS exome

AF:

0.0135

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

Gnomad4 AFR exome

AF:

0.00296

Gnomad4 AMR exome

AF:

0.0427

Gnomad4 ASJ exome

AF:

0.0141

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0137

Gnomad4 FIN exome

AF:

0.00256

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0150

GnomAD4 genome

AF:

0.0126

AC:

1913

AN:

152190

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

910

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00455

Gnomad4 AMR

AF:

0.0215

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.0147

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	FZD4: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2018	This variant is associated with the following publications: (PMID: 21179236, 28982955, 24744206, 27535533, 15733276, 15223780, 22995991) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Exudative vitreoretinopathy 1

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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% -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2014	- -

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

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

MutationTaster

Benign

1.0e-8

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over