chr11-86946478-A-G

Variant names:

• chr11-86946478-A-G
• rs713065
• NM_012193.4:c.*4664T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.286
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
FZD4	NM_012193.4	c.*4664T>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000531380.2	NP_036325.2
PRSS23	NR_120591.3	n.435-3878A>G		intron_variant	Intron 3 of 4
PRSS23	NR_120592.2	n.328-4738A>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2	c.*4664T>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_012193.4	ENSP00000434034.1

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AF: 0.625 AC: 5 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.525 AC: 21 AN: 40

Other (OTH) AF: 0.500 AC: 2 AN: 4

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

African (AFR) AF: 0.466 AC: 19313 AN: 41448

American (AMR) AF: 0.578 AC: 8833 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2270 AN: 3466

East Asian (EAS) AF: 0.435 AC: 2245 AN: 5156

South Asian (SAS) AF: 0.498 AC: 2400 AN: 4820

European-Finnish (FIN) AF: 0.570 AC: 6000 AN: 10534

Middle Eastern (MID) AF: 0.709 AC: 207 AN: 292

European-Non Finnish (NFE) AF: 0.631 AC: 42889 AN: 67960

Other (OTH) AF: 0.598 AC: 1264 AN: 2112

Alfa AF: 0.616 Hom.: 84507

Bravo AF: 0.565

Asia WGS AF: 0.469 AC: 1632 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Exudative vitreoretinopathy 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs713065; hg19: chr11-86657520;