dbSNP rs12549394: FZD6:p.Ala664Glu (chr8-103331379-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

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

BP6

Variant 8-103331379-C-A is Benign according to our data. Variant chr8-103331379-C-A is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.0135

AC:

3396

AN:

251476

Hom.:

141

AF XY:

0.0108

AC XY:

1466

AN XY:

135902

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 SAS exome

AF:

0.000261

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

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.0801

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0245

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000801

Gnomad4 OTH exome

AF:

0.00340

GnomAD4 genome

AF:

0.00731

AC:

1112

AN:

152208

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

617

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00202

Gnomad4 AMR

AF:

0.0576

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0199

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.0105

Alfa

AF:

0.00188

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

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;.

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over