rs713065

chr11-86946478-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012193.4(FZD4):c.*4664T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 152,044 control chromosomes in the GnomAD database, including 24,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (24796 hom., cov: 32)
  • Exomes 𝑓: 0.53 (7 hom.)
• Consequence: FZD4 NM_012193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.286

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-86946478-A-G is Benign according to our data. Variant chr11-86946478-A-G is described in ClinVar as [Benign]. Clinvar id is 306335.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD4	NM_012193.4	c.*4664T>C		3_prime_UTR_variant	2/2	ENST00000531380.2
PRSS23	NR_120591.3	n.435-3878A>G		intron_variant, non_coding_transcript_variant
PRSS23	NR_120592.2	n.328-4738A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD4	ENST00000531380.2	c.*4664T>C		3_prime_UTR_variant	2/2	1	NM_012193.4	P1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86079 AN: 151870 Hom.: 24795 Cov.: 32

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.606

GnomAD4 exome AF: 0.534 AC: 31 AN: 58 Hom.: 7 Cov.: 0 AF XY: 0.536 AC XY: 15 AN XY: 28

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.625

Gnomad4 NFE exome AF: 0.525

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.567 AC: 86102 AN: 151986 Hom.: 24796 Cov.: 32 AF XY: 0.562 AC XY: 41773 AN XY: 74300

Gnomad4 AFR AF: 0.466

Gnomad4 AMR AF: 0.578

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.498

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.631

Gnomad4 OTH AF: 0.598

Alfa AF: 0.618 Hom.: 58691

Bravo AF: 0.565

Asia WGS AF: 0.469 AC: 1632 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.4
Dann	Benign	0.75

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: rs713065; hg19: chr11-86657520;