11-86951506-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_012193.4(FZD4):c.1250G>A(p.Arg417Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R417W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FZD4 NM_012193.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical; Name=5 (size 34) in uniprot entity FZD4_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_012193.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 11-86951506-C-T is Pathogenic according to our data. Variant chr11-86951506-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5486.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-86951506-C-T is described in Lovd as [Pathogenic]. Variant chr11-86951506-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD4	NM_012193.4	c.1250G>A	p.Arg417Gln	missense_variant	2/2	ENST00000531380.2
PRSS23	NR_120591.3	n.869C>T		non_coding_transcript_exon_variant	5/5
PRSS23	NR_120592.2	n.618C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD4	ENST00000531380.2	c.1250G>A	p.Arg417Gln	missense_variant	2/2	1	NM_012193.4	P1
PRSS23	ENST00000532234.5	c.*499C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
PRSS23	ENST00000533902.2	c.*221C>T		3_prime_UTR_variant	3/3	4
PRSS23	ENST00000531521.1	n.677C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251492 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Exudative vitreoretinopathy, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2005

- -

Exudative vitreoretinopathy 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.95		Gain of ubiquitination at K422 (P = 0.0291);
MVP		0.97
MPC		1.0
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.87

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: rs80358294; hg19: chr11-86662548;