rs80358302

Variant names:

• chr11-86951257-GTT-G
• NM_012193.4:c.1497_1498delAA

Your query was ambiguous. Multiple possible variants found:

• chr11-86951257-GTT-G
• chr11-86951257-GTT-GT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_012193.4(FZD4):​c.1497_1498delAA​(p.Lys499AsnfsTer35) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FZD4 NM_012193.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.96

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 Likely_pathogenic. Variant got 8 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-86951257-GTT-G is Pathogenic according to our data. Variant chr11-86951257-GTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 2760685.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD4	NM_012193.4	c.1497_1498delAA	p.Lys499AsnfsTer35	frameshift_variant	Exon 2 of 2	ENST00000531380.2	NP_036325.2
PRSS23	NR_120591.3	n.623_624delTT		non_coding_transcript_exon_variant	Exon 5 of 5
PRSS23	NR_120592.2	n.372_373delTT		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2	c.1497_1498delAA	p.Lys499AsnfsTer35	frameshift_variant	Exon 2 of 2	1	NM_012193.4	ENSP00000434034.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with FZD4-related conditions. 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). 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 variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys499Asnfs*35) in the FZD4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the FZD4 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-86662299;