rs10898563

Variant names:

• chr11-86948171-A-G
• rs10898563
• NM_012193.4:c.*2971T>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.*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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.417
• Publications: 28 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=-0.79).
• 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
FZD4	NM_012193.4	c.*2971T>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000531380.2	NP_036325.2
PRSS23	NR_120591.3	n.435-2185A>G		intron_variant	Intron 3 of 4
PRSS23	NR_120592.2	n.328-3045A>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2	c.*2971T>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_012193.4	ENSP00000434034.1

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

African (AFR) AF: 0.167 AC: 1 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 1.00 AC: 4 AN: 4

European-Non Finnish (NFE) AF: 0.348 AC: 16 AN: 46

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

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

African (AFR) AF: 0.0929 AC: 3848 AN: 41410

American (AMR) AF: 0.269 AC: 4111 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1383 AN: 3468

East Asian (EAS) AF: 0.0944 AC: 487 AN: 5160

South Asian (SAS) AF: 0.238 AC: 1146 AN: 4814

European-Finnish (FIN) AF: 0.360 AC: 3799 AN: 10556

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.380 AC: 25838 AN: 67918

Other (OTH) AF: 0.308 AC: 648 AN: 2106

Alfa AF: 0.344 Hom.: 24621

Bravo AF: 0.263

Asia WGS AF: 0.124 AC: 435 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	-0.79
CADD	Benign	4.7
DANN	Benign	0.77
PhyloP100		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10898563; hg19: chr11-86659213;