rs80358289

Variant names:

• chr11-86952078-C-G
• NM_012193.4:c.678G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-86952078-C-G
• chr11-86952078-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_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
• Clinical Significance: Not reported in ClinVar
• 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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 30) in uniprot entity FZD4_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_012193.4
• 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-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD4	NM_012193.4	c.678G>C	p.Trp226Cys	missense_variant	Exon 2 of 2	ENST00000531380.2	NP_036325.2
PRSS23	NR_120591.3	n.1441C>G		non_coding_transcript_exon_variant	Exon 5 of 5
PRSS23	NR_120592.2	n.1190C>G		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2	c.678G>C	p.Trp226Cys	missense_variant	Exon 2 of 2	1	NM_012193.4	ENSP00000434034.1
PRSS23	ENST00000532234.5	n.*1071C>G		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000436676.1
PRSS23	ENST00000532234.5	n.*1071C>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000436676.1
PRSS23	ENST00000533902.2	c.*793C>G		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000437268.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.7	L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.018	D
Polyphen		0.98	D
Vest4		0.91
MutPred		0.84		Gain of catalytic residue at S228 (P = 0.1885);
MVP		0.79
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-86663120;