rs80358295

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_012193.4(FZD4):c.1282_1285del(p.Asp428SerfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

FZD4
NM_012193.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.96

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 42 pathogenic variants in the truncated region.

PP5

Variant 11-86951470-TTGTC-T is Pathogenic according to our data. Variant chr11-86951470-TTGTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86951470-TTGTC-T is described in Lovd as [Pathogenic]. Variant chr11-86951470-TTGTC-T is described in Lovd as [Likely_pathogenic]. Variant chr11-86951470-TTGTC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FZD4	NM_012193.4 linkuse as main transcript	c.1282_1285del	p.Asp428SerfsTer2	frameshift_variant	2/2	ENST00000531380.2
PRSS23	NR_120591.3 linkuse as main transcript	n.839_842del		non_coding_transcript_exon_variant	5/5
PRSS23	NR_120592.2 linkuse as main transcript	n.588_591del		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FZD4	ENST00000531380.2 linkuse as main transcript	c.1282_1285del	p.Asp428SerfsTer2	frameshift_variant	2/2	1	NM_012193.4	P1
PRSS23	ENST00000532234.5 linkuse as main transcript	c.469_472del		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
PRSS23	ENST00000533902.2 linkuse as main transcript	c.191_194del		3_prime_UTR_variant	3/3	4
PRSS23	ENST00000531521.1 linkuse as main transcript	n.647_650del		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251490

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461778

Hom.:

AF XY:

0.0000206

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2022	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 110 amino acids are lost and replaced with one incorrect amino acid; This variant is associated with the following publications: (PMID: 20340138, 28494495, 30097784, 31827910, 31987760, 31299183, 33090715, 32238352, 33302760, 30452590) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	This sequence change creates a premature translational stop signal (p.Asp428Serfs*2) in the FZD4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 110 amino acid(s) of the FZD4 protein. This variant is present in population databases (rs80358295, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with familial exudative vitreoretinopathy (PMID: 20340138, 28494495, 30452590). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224625). For these reasons, this variant has been classified as Pathogenic. -

Exudative vitreoretinopathy 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported to be associated with FZD4 related disorder (ClinVar ID: VCV000224625 / PMID: 20340138). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 28, 2022	- -

Exudative retinopathy;C0339539:Familial exudative vitreoretinopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Human Molecular Genetics, Department of Medical Research, Taipei Veterans General Hospital

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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