rs61735303

Positions:

• chr11-86952254-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a topological_domain Extracellular (size 175) in uniprot entity FZD4_HUMAN there are 69 pathogenic changes around while only 7 benign (91%) in NM_012193.4
• 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	UniProt
FZD4	NM_012193.4	c.502C>T	p.Pro168Ser	missense_variant	2/2	ENST00000531380.2
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	Appris	UniProt
FZD4	ENST00000531380.2	c.502C>T	p.Pro168Ser	missense_variant	2/2	1	NM_012193.4	P1
PRSS23	ENST00000532234.5	c.*1247G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
PRSS23	ENST00000533902.2	c.*969G>A		3_prime_UTR_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2176 AN: 152176 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00941

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0184 AC: 4625 AN: 251466 Hom.: 86 AF XY: 0.0174 AC XY: 2363 AN XY: 135908

Gnomad AFR exome AF: 0.00880

Gnomad AMR exome AF: 0.0474

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0210

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0188 AC: 27444 AN: 1461856 Hom.: 331 Cov.: 33 AF XY: 0.0184 AC XY: 13400 AN XY: 727228

Gnomad4 AFR exome AF: 0.00950

Gnomad4 AMR exome AF: 0.0434

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.00264

Gnomad4 NFE exome AF: 0.0196

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0144 AC: 2186 AN: 152294 Hom.: 22 Cov.: 33 AF XY: 0.0140 AC XY: 1040 AN XY: 74486

Gnomad4 AFR AF: 0.00950

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0182 Hom.: 41

Bravo AF: 0.0162

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00863 AC: 38

ESP6500EA AF: 0.0180 AC: 155

ExAC AF: 0.0166 AC: 2018

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0173

EpiControl AF: 0.0169

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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	Invitae	Jan 31, 2024	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.026
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.086	T
Sift4G	Benign	0.071	T
Polyphen		0.15	B
Vest4		0.12
MPC		0.29
ClinPred		0.015	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.56

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: rs61735303; hg19: chr11-86663296;