rs10898563

chr11-86948171-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.*2971T>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 0.276 in 151,960 control chromosomes in the GnomAD database, including 7,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (7129 hom., cov: 31)
  • Exomes 𝑓: 0.39 (5 hom.)
• Consequence: FZD4 NM_012193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.417

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=-0.79).
• BP6: Variant 11-86948171-A-G is Benign according to our data. Variant chr11-86948171-A-G is described in ClinVar as [Benign]. Clinvar id is 306365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD4	NM_012193.4	c.*2971T>C		3_prime_UTR_variant	2/2	ENST00000531380.2
PRSS23	NR_120591.3	n.435-2185A>G		intron_variant, non_coding_transcript_variant
PRSS23	NR_120592.2	n.328-3045A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD4	ENST00000531380.2	c.*2971T>C		3_prime_UTR_variant	2/2	1	NM_012193.4	P1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41857 AN: 151780 Hom.: 7128 Cov.: 31

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.311

GnomAD4 exome AF: 0.387 AC: 24 AN: 62 Hom.: 5 Cov.: 0 AF XY: 0.450 AC XY: 18 AN XY: 40

Gnomad4 AFR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.500

Gnomad4 NFE exome AF: 0.348

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.275 AC: 41847 AN: 151898 Hom.: 7129 Cov.: 31 AF XY: 0.272 AC XY: 20208 AN XY: 74210

Gnomad4 AFR AF: 0.0929

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.0944

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.308

Alfa AF: 0.362 Hom.: 10559

Bravo AF: 0.263

Asia WGS AF: 0.124 AC: 435 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	-0.79
Cadd	Benign	4.7
Dann	Benign	0.77
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: rs10898563; hg19: chr11-86659213;