chr8-103300153-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003506.4(FZD6):c.46C>G(p.Leu16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,602,314 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 25 hom. )

Consequence

FZD6
NM_003506.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -4.14

Variant links:

Genes affected

FZD6 (HGNC:4044): (frizzled class receptor 6) This gene represents a member of the 'frizzled' gene family, which encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The protein encoded by this family member contains a signal peptide, a cysteine-rich domain in the N-terminal extracellular region, and seven transmembrane domains, but unlike other family members, this protein does not contain a C-terminal PDZ domain-binding motif. This protein functions as a negative regulator of the canonical Wnt/beta-catenin signaling cascade, thereby inhibiting the processes that trigger oncogenic transformation, cell proliferation, and inhibition of apoptosis. Alternative splicing results in multiple transcript variants, some of which do not encode a protein with a predicted signal peptide.[provided by RefSeq, Aug 2011]

FZD6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041077137).

BP6

Variant 8-103300153-C-G is Benign according to our data. Variant chr8-103300153-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3039484.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.003 (457/152242) while in subpopulation NFE AF = 0.00526 (358/68012). AF 95% confidence interval is 0.00481. There are 0 homozygotes in GnomAd4. There are 202 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD6	NM_003506.4 link	c.46C>G	p.Leu16Val	missense_variant	Exon 2 of 7	ENST00000358755.5	NP_003497.2	O60353-1A0A024R9E9B4E236

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD6	ENST00000358755.5 link	c.46C>G	p.Leu16Val	missense_variant	Exon 2 of 7	1	NM_003506.4	ENSP00000351605.4		O60353-1

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

457

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.0330

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00526

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00306

AC:

769

AN:

251448

AF XY:

0.00302

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00602

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00479

AC:

6949

AN:

1450072

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

3420

AN XY:

722144

show subpopulations

Gnomad4 AFR exome

AF:

0.000541

AC:

AN:

33284

Gnomad4 AMR exome

AF:

0.000828

AC:

AN:

44708

Gnomad4 ASJ exome

AF:

0.000230

AC:

AN:

26078

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39630

Gnomad4 SAS exome

AF:

0.000174

AC:

AN:

86016

Gnomad4 FIN exome

AF:

0.00152

AC:

AN:

53416

Gnomad4 NFE exome

AF:

0.00602

AC:

6624

AN:

1101192

Gnomad4 Remaining exome

AF:

0.00280

AC:

168

AN:

59994

Heterozygous variant carriers

323

646

968

1291

1614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.00300

AC:

457

AN:

152242

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

202

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000963

AC:

0.000963159

AN:

0.000963159

Gnomad4 AMR

AF:

0.000588

AC:

0.000588389

AN:

0.000588389

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00104

AC:

0.00103563

AN:

0.00103563

Gnomad4 FIN

AF:

0.00104

AC:

0.00103754

AN:

0.00103754

Gnomad4 NFE

AF:

0.00526

AC:

0.00526378

AN:

0.00526378

Gnomad4 OTH

AF:

0.00189

AC:

0.00189394

AN:

0.00189394

Heterozygous variant carriers

114

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:

0.00424

Hom.:

Bravo

AF:

0.00305

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00358

AC:

434

EpiCase

AF:

0.00458

EpiControl

AF:

0.00522

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

FZD6-related disorder

Benign:1

Jan 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.0020

DANN

Benign

0.54

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.039

.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.64

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

0.58

N;N

REVEL

Benign

0.20

Sift

Benign

0.80

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.018

MVP

0.52

MPC

0.26

ClinPred

0.0023

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.034

gMVP

0.33

Mutation Taster

=99/1

polymorphism

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

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