chr11-86952443-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM5PP3BS2

The NM_012193.4(FZD4):c.313A>T(p.Met105Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,594 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M105V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

FZD4
NM_012193.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.27

Publications

40 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_benign. The variant received -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-86952443-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 224624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

BS2

High AC in GnomAdExome4 at 14 SD,AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FZD4	NM_012193.4 link	c.313A>T	p.Met105Leu	missense_variant	Exon 2 of 2	ENST00000531380.2	NP_036325.2
PRSS23	NR_120591.3 link	n.1806T>A		non_coding_transcript_exon_variant	Exon 5 of 5
PRSS23	NR_120592.2 link	n.1555T>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FZD4	ENST00000531380.2 link	c.313A>T	p.Met105Leu	missense_variant	Exon 2 of 2	1	NM_012193.4	ENSP00000434034.1
PRSS23	ENST00000532234.5 link	n.*1436T>A		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000436676.1
PRSS23	ENST00000532234.5 link	n.*1436T>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000436676.1
PRSS23	ENST00000533902.2 link	c.*1158T>A		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000437268.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250246

AF XY:

0.00000738

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461594

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111868

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.053

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

-0.054

MutationAssessor

Uncertain

2.1

PhyloP100

6.3

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.51

Sift

Benign

0.046

Sift4G

Benign

0.069

Polyphen

0.90

Vest4

0.61

MutPred

0.65

Gain of catalytic residue at M105 (P = 0.0784);

MVP

0.68

MPC

0.35

ClinPred

0.46

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.69

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over