NM_012193.4:c.502C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012193.4(FZD4):c.502C>T(p.Pro168Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,614,150 control chromosomes in the GnomAD database, including 353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 22 hom., cov: 33)

Exomes 𝑓: 0.019 ( 331 hom. )

Consequence

FZD4
NM_012193.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.52

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:

PRSS23 (HGNC:14370): (serine protease 23) This gene encodes a conserved member of the trypsin family of serine proteases. Mouse studies found a decrease of mRNA levels of this gene after ovulation was induced. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

PRSS23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032744408).

BP6

Variant 11-86952254-G-A is Benign according to our data. Variant chr11-86952254-G-A is described in ClinVar as [Benign]. Clinvar id is 306407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86952254-G-A is described in Lovd as [Benign]. Variant chr11-86952254-G-A is described in Lovd as [Pathogenic]. Variant chr11-86952254-G-A is described in Lovd as [Likely_benign]. Variant chr11-86952254-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0144 (2186/152294) while in subpopulation SAS AF= 0.0261 (126/4828). AF 95% confidence interval is 0.0224. There are 22 homozygotes in gnomad4. There are 1040 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2186 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD4	NM_012193.4 link	c.502C>T	p.Pro168Ser	missense_variant	Exon 2 of 2	ENST00000531380.2	NP_036325.2	Q9ULV1
PRSS23	NR_120591.3 link	n.1617G>A		non_coding_transcript_exon_variant	Exon 5 of 5
PRSS23	NR_120592.2 link	n.1366G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FZD4	ENST00000531380.2 link	c.502C>T	p.Pro168Ser	missense_variant	Exon 2 of 2	1	NM_012193.4	ENSP00000434034.1	Q9ULV1
PRSS23	ENST00000532234.5 link	n.*1247G>A		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000436676.1	E9PIB7
PRSS23	ENST00000532234.5 link	n.*1247G>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000436676.1	E9PIB7
PRSS23	ENST00000533902.2 link	c.*969G>A		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000437268.1	E9PMX2

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2176

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00941

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0223

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0184

AC:

4625

AN:

251466

Hom.:

AF XY:

0.0174

AC XY:

2363

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00880

Gnomad AMR exome

AF:

0.0474

Gnomad ASJ exome

AF:

0.0145

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0210

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0188

AC:

27444

AN:

1461856

Hom.:

331

Cov.:

AF XY:

0.0184

AC XY:

13400

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00950

Gnomad4 AMR exome

AF:

0.0434

Gnomad4 ASJ exome

AF:

0.0143

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0213

Gnomad4 FIN exome

AF:

0.00264

Gnomad4 NFE exome

AF:

0.0196

Gnomad4 OTH exome

AF:

0.0166

GnomAD4 genome

AF:

0.0144

AC:

2186

AN:

152294

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1040

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00950

Gnomad4 AMR

AF:

0.0222

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0261

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.0176

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0182

Hom.:

Bravo

AF:

0.0162

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00863

AC:

ESP6500EA

AF:

0.0180

AC:

155

ExAC

AF:

0.0166

AC:

2018

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0173

EpiControl

AF:

0.0169

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15223780, 31114654, 28982955) -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: 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 -

Exudative vitreoretinopathy 1

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

Eigen

Benign

0.026

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.33

Sift

Benign

0.086

Sift4G

Benign

0.071

Polyphen

0.15

Vest4

0.12

MPC

0.29

ClinPred

0.015

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.56

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