rs80358290

chr11-86951798-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_012193.4(FZD4):c.957del(p.Trp319CysfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FZD4 NM_012193.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 64 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-86951798-AC-A is Pathogenic according to our data. Variant chr11-86951798-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2137212.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-86951798-AC-A is described in Lovd as [Pathogenic]. Variant chr11-86951798-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD4	NM_012193.4	c.957del	p.Trp319CysfsTer5	frameshift_variant	2/2	ENST00000531380.2
PRSS23	NR_120591.3	n.1163del		non_coding_transcript_exon_variant	5/5
PRSS23	NR_120592.2	n.912del		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD4	ENST00000531380.2	c.957del	p.Trp319CysfsTer5	frameshift_variant	2/2	1	NM_012193.4	P1
PRSS23	ENST00000532234.5	c.*793del		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
PRSS23	ENST00000533902.2	c.*515del		3_prime_UTR_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 12, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FZD4 protein in which other variant(s) (p.Gln505*) have been determined to be pathogenic (PMID: 15223780, 23077402). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with familial exudative vitreoretinopathy (PMID: 15223780). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp319Cysfs*5) in the FZD4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 219 amino acid(s) of the FZD4 protein. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs80358290; hg19: chr11-86662840;