rs104894223

Positions:

chr11-86951990-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_012193.4(FZD4):c.766A>G(p.Ile256Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,613,952 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 1 hom. )

Consequence

FZD4
NM_012193.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:1

Conservation

PhyloP100: 8.02

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:

PRSS23 (HGNC:):

PRSS23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a disulfide_bond (size 78) in uniprot entity FZD4_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_012193.4

BS2

High AC in GnomAd4 at 78 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD4	NM_012193.4 linkuse as main transcript	c.766A>G	p.Ile256Val	missense_variant	2/2	ENST00000531380.2	NP_036325.2	Q9ULV1
PRSS23	NR_120591.3 linkuse as main transcript	n.1353T>C		non_coding_transcript_exon_variant	5/5
PRSS23	NR_120592.2 linkuse as main transcript	n.1102T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FZD4	ENST00000531380.2 linkuse as main transcript	c.766A>G	p.Ile256Val	missense_variant	2/2	1	NM_012193.4	ENSP00000434034.1	Q9ULV1
PRSS23	ENST00000532234.5 linkuse as main transcript	n.*983T>C		non_coding_transcript_exon_variant	5/5	1		ENSP00000436676.1	E9PIB7
PRSS23	ENST00000532234.5 linkuse as main transcript	n.*983T>C		3_prime_UTR_variant	5/5	1		ENSP00000436676.1	E9PIB7
PRSS23	ENST00000533902.2 linkuse as main transcript	c.*705T>C		3_prime_UTR_variant	3/3	4		ENSP00000437268.1	E9PMX2

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000510

AC:

128

AN:

251216

Hom.:

AF XY:

0.000626

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000871

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000521

AC:

762

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

382

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.000618

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000513

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000944

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.0220

Hom.:

2351

Bravo

AF:

0.000408

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinopathy of prematurity

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Exudative vitreoretinopathy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

FZD4-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

The FZD4 c.766A>G variant is predicted to result in the amino acid substitution p.Ile256Val. This variant has been reported in an individual with retinopathy of prematurity (MacDonald et al 2005. PubMed ID: 15733276). This variant is reported in 0.088% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual in the latest dataset (https://gnomad.broadinstitute.org/variant/11-86951990-T-C?dataset=gnomad_r4). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.92

REVEL

Uncertain

0.61

Sift

Benign

0.11

Sift4G

Benign

0.17

Polyphen

0.94

Vest4

0.79

MVP

0.85

MPC

0.54

ClinPred

0.088

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.56

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

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