11-86946065-G-C

Position:

• chr11-86946065-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_012193.4(FZD4):​c.*5077C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 152,516 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (52 hom., cov: 32)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: FZD4 NM_012193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.04

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]

PRSS23 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-86946065-G-C is Benign according to our data. Variant chr11-86946065-G-C is described in ClinVar as [Benign]. Clinvar id is 306329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0204 (3106/152114) while in subpopulation NFE AF= 0.0284 (1931/68010). AF 95% confidence interval is 0.0273. There are 52 homozygotes in gnomad4. There are 1490 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3106 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD4	NM_012193.4	c.*5077C>G		3_prime_UTR_variant	2/2	ENST00000531380.2	NP_036325.2
PRSS23	NR_120591.3	n.435-4291G>C		intron_variant
PRSS23	NR_120592.2	n.328-5151G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380	c.*5077C>G		3_prime_UTR_variant	2/2	1	NM_012193.4	ENSP00000434034.1

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3108 AN: 151996 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.00493

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00706

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0296

GnomAD4 exome AF: 0.0199 AC: 8 AN: 402 Hom.: 0 Cov.: 0 AF XY: 0.0168 AC XY: 4 AN XY: 238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.0500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0204 AC: 3106 AN: 152114 Hom.: 52 Cov.: 32 AF XY: 0.0200 AC XY: 1490 AN XY: 74348

Gnomad4 AFR AF: 0.00492

Gnomad4 AMR AF: 0.0274

Gnomad4 ASJ AF: 0.0438

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00727

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.0284

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.00543 Hom.: 0

Bravo AF: 0.0212

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Exudative vitreoretinopathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs143372848; hg19: chr11-86657107;