dbSNP rs12549394: FZD6:p.Ala664Glu (chr8-103331379-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003506.4(FZD6):c.1991C>A(p.Ala664Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,612,490 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0073 ( 39 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 183 hom. )

Consequence

FZD6
NM_003506.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.384

Publications

14 publications found

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:

BAALC-AS1 (HGNC:50461): (BAALC antisense RNA 1)

BAALC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021431744).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD6	NM_003506.4 link	c.1991C>A	p.Ala664Glu	missense_variant	Exon 7 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.1991C>A	p.Ala664Glu	missense_variant	Exon 7 of 7	1	NM_003506.4	ENSP00000351605.4		O60353-1

Frequencies

GnomAD3 genomes

AF:

0.00733

AC:

1115

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0579

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0196

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0135

AC:

3396

AN:

251476

AF XY:

0.0108

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.0825

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0225

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00336

AC:

4903

AN:

1460282

Hom.:

183

Cov.:

AF XY:

0.00298

AC XY:

2163

AN XY:

726544

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33452

American (AMR)

AF:

0.0801

AC:

3584

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0245

AC:

972

AN:

39684

South Asian (SAS)

AF:

0.000186

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000801

AC:

AN:

1110548

Other (OTH)

AF:

0.00340

AC:

205

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

297

595

892

1190

1487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00731

AC:

1112

AN:

152208

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

617

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

41540

American (AMR)

AF:

0.0576

AC:

881

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0199

AC:

103

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68010

Other (OTH)

AF:

0.0105

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00244

Hom.:

Bravo

AF:

0.0116

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0103

AC:

1245

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.0090

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.16

T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.53

.;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

-0.38

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.29

N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.019

D;D;D

Sift4G

Benign

0.33

T;T;T

Polyphen

0.012

B;B;.

Vest4

0.065

MPC

0.31

ClinPred

0.0018

GERP RS

-8.1

Varity_R

0.076

gMVP

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over