GeneBe

rs80358293

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_012193.4(FZD4):​c.1024A>T​(p.Met342Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. M342I) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

FZD4
NM_012193.4 missense

Scores

1
8
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.13
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a disulfide_bond (size 75) 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 chr11-86951730-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.4059527).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FZD4NM_012193.4 linkc.1024A>T p.Met342Leu missense_variant Exon 2 of 2 ENST00000531380.2 NP_036325.2 Q9ULV1
PRSS23NR_120591.3 linkn.1095T>A non_coding_transcript_exon_variant Exon 5 of 5
PRSS23NR_120592.2 linkn.844T>A non_coding_transcript_exon_variant Exon 3 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FZD4ENST00000531380.2 linkc.1024A>T p.Met342Leu missense_variant Exon 2 of 2 1 NM_012193.4 ENSP00000434034.1 Q9ULV1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Uncertain
0.037
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
23
DANN
Uncertain
0.97
DEOGEN2
Benign
0.37
T
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-0.83
N
REVEL
Benign
0.12
Sift
Uncertain
0.011
D
Sift4G
Uncertain
0.043
D
Polyphen
0.43
B
Vest4
0.61
MutPred
0.49
Loss of disorder (P = 0.1123);
MVP
0.53
MPC
0.49
ClinPred
0.61
D
GERP RS
5.6
Varity_R
0.64
gMVP
0.48

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: chr11-86662774; API