Genetic Variant FZD4:p.Trp226Cys (chr11-86952078-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_012193.4(FZD4):c.678G>C(p.Trp226Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W226R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

FZD4
NM_012193.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

1 publications found

Variant links:

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]

FZD4 links:

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]

PRSS23 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-86952080-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 418221.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012193.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FZD4	NM_012193.4	MANE Select	c.678G>C	p.Trp226Cys	missense	Exon 2 of 2	NP_036325.2
PRSS23	NR_120591.3		n.1441C>G		non_coding_transcript_exon	Exon 5 of 5
PRSS23	NR_120592.2		n.1190C>G		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FZD4	ENST00000531380.2	TSL:1 MANE Select	c.678G>C	p.Trp226Cys	missense	Exon 2 of 2	ENSP00000434034.1
PRSS23	ENST00000532234.5	TSL:1	n.*1071C>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000436676.1
PRSS23	ENST00000532234.5	TSL:1	n.*1071C>G		3_prime_UTR	Exon 5 of 5	ENSP00000436676.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

1.7

PhyloP100

7.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.83

Sift

Uncertain

0.020

Sift4G

Uncertain

0.018

Polyphen

0.98

Vest4

0.91

MutPred

0.84

Gain of catalytic residue at S228 (P = 0.1885)

MVP

0.79

MPC

1.1

ClinPred

1.0

GERP RS

5.7

Varity_R

0.91

gMVP

0.98

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over