rs80358282

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM1BP4_ModerateBS1BS2

The NM_012193.4(FZD4):c.205C>T(p.His69Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000314 in 1,613,404 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

FZD4
NM_012193.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.85

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM1

In a disulfide_bond (size 61) in uniprot entity FZD4_HUMAN there are 35 pathogenic changes around while only 2 benign (95%) in NM_012193.4

BP4

Computational evidence support a benign effect (MetaRNN=0.10089463).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000323 (472/1461182) while in subpopulation EAS AF = 0.00703 (279/39684). AF 95% confidence interval is 0.00635. There are 2 homozygotes in GnomAdExome4. There are 237 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 34 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD4	NM_012193.4 link	c.205C>T	p.His69Tyr	missense_variant	Exon 1 of 2	ENST00000531380.2	NP_036325.2	Q9ULV1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2 link	c.205C>T	p.His69Tyr	missense_variant	Exon 1 of 2	1	NM_012193.4	ENSP00000434034.1		Q9ULV1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00369

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000520

AC:

128

AN:

246338

AF XY:

0.000515

show subpopulations

Gnomad AFR exome

AF:

0.0000639

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.00428

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000327

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000323

AC:

472

AN:

1461182

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

237

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.0000895

AC:

AN:

44714

Gnomad4 ASJ exome

AF:

0.000383

AC:

AN:

26112

Gnomad4 EAS exome

AF:

0.00703

AC:

279

AN:

39684

Gnomad4 SAS exome

AF:

0.000139

AC:

AN:

86214

Gnomad4 FIN exome

AF:

0.000189

AC:

AN:

53026

Gnomad4 NFE exome

AF:

0.000128

AC:

142

AN:

1111862

Gnomad4 Remaining exome

AF:

0.000215

AC:

AN:

60326

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.000223

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000131

AC:

0.000130634

AN:

0.000130634

Gnomad4 ASJ

AF:

0.000288

AC:

0.000288351

AN:

0.000288351

Gnomad4 EAS

AF:

0.00370

AC:

0.0036965

AN:

0.0036965

Gnomad4 SAS

AF:

0.000415

AC:

0.000414938

AN:

0.000414938

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000147

AC:

0.000147128

AN:

0.000147128

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome 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

Alfa

AF:

0.000556

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000528

AC:

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Exudative vitreoretinopathy 1

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2017

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 14, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.10

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.9

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.011

Polyphen

0.20

Vest4

0.82

MVP

0.74

MPC

1.0

ClinPred

0.16

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.92

gMVP

0.91

Mutation Taster

=74/26

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over