rs61735303
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_012193.4(FZD4):c.502C>T(p.Pro168Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,614,150 control chromosomes in the GnomAD database, including 353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.014 ( 22 hom., cov: 33)
Exomes 𝑓: 0.019 ( 331 hom. )
Consequence
FZD4
NM_012193.4 missense
NM_012193.4 missense
Scores
5
13
Clinical Significance
Conservation
PhyloP100: 6.52
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0032744408).
BP6
Variant 11-86952254-G-A is Benign according to our data. Variant chr11-86952254-G-A is described in ClinVar as [Benign]. Clinvar id is 306407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86952254-G-A is described in Lovd as [Benign]. Variant chr11-86952254-G-A is described in Lovd as [Pathogenic]. Variant chr11-86952254-G-A is described in Lovd as [Likely_benign]. Variant chr11-86952254-G-A is described in Lovd as [Likely_pathogenic].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0144 (2186/152294) while in subpopulation SAS AF= 0.0261 (126/4828). AF 95% confidence interval is 0.0224. There are 22 homozygotes in gnomad4. There are 1040 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 2186 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FZD4 | NM_012193.4 | c.502C>T | p.Pro168Ser | missense_variant | 2/2 | ENST00000531380.2 | NP_036325.2 | |
PRSS23 | NR_120591.3 | n.1617G>A | non_coding_transcript_exon_variant | 5/5 | ||||
PRSS23 | NR_120592.2 | n.1366G>A | non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FZD4 | ENST00000531380.2 | c.502C>T | p.Pro168Ser | missense_variant | 2/2 | 1 | NM_012193.4 | ENSP00000434034 | P1 | |
PRSS23 | ENST00000532234.5 | c.*1247G>A | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 | 1 | ENSP00000436676 | ||||
PRSS23 | ENST00000533902.2 | c.*969G>A | 3_prime_UTR_variant | 3/3 | 4 | ENSP00000437268 |
Frequencies
GnomAD3 genomes AF: 0.0143 AC: 2176AN: 152176Hom.: 21 Cov.: 33
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GnomAD3 exomes AF: 0.0184 AC: 4625AN: 251466Hom.: 86 AF XY: 0.0174 AC XY: 2363AN XY: 135908
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GnomAD4 exome AF: 0.0188 AC: 27444AN: 1461856Hom.: 331 Cov.: 33 AF XY: 0.0184 AC XY: 13400AN XY: 727228
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GnomAD4 genome AF: 0.0144 AC: 2186AN: 152294Hom.: 22 Cov.: 33 AF XY: 0.0140 AC XY: 1040AN XY: 74486
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 15223780, 31114654, 28982955) - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency - |
Exudative vitreoretinopathy 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at