rs80358289

Positions:

• chr11-86952078-C-T

Variant summary

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

The NM_012193.4(FZD4):​c.678G>A​(p.Trp226Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FZD4 NM_012193.4 stop_gained
• 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 69 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-86952078-C-T is Pathogenic according to our data. Variant chr11-86952078-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 940196.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-86952078-C-T is described in Lovd as [Pathogenic]. Variant chr11-86952078-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-86952078-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD4	NM_012193.4	c.678G>A	p.Trp226Ter	stop_gained	2/2	ENST00000531380.2	NP_036325.2
PRSS23	NR_120591.3	n.1441C>T		non_coding_transcript_exon_variant	5/5
PRSS23	NR_120592.2	n.1190C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2	c.678G>A	p.Trp226Ter	stop_gained	2/2	1	NM_012193.4	ENSP00000434034	P1
PRSS23	ENST00000532234.5	c.*1071C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	1		ENSP00000436676
PRSS23	ENST00000533902.2	c.*793C>T		3_prime_UTR_variant	3/3	4		ENSP00000437268

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects FZD4 function (PMID: 21177847). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 940196). This premature translational stop signal has been observed in individuals with FZD4-related conditions (PMID: 21097938, 21177847). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp226*) in the FZD4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 312 amino acid(s) of the FZD4 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.82
GERP RS		5.7

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

Other links and lift over

dbSNP: rs80358289; hg19: chr11-86663120;