Variant chr10-35639391-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031866.3(FZD8):c.2039C>G(p.Ala680Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000951 in 1,472,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

FZD8
NM_031866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

Variant links:

Genes affected

FZD8 (HGNC:4046): (frizzled class receptor 8) This intronless 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 gene is highly expressed in two human cancer cell lines, indicating that it may play a role in several types of cancer. The crystal structure of the extracellular cysteine-rich domain of a similar mouse protein has been determined. [provided by RefSeq, Jul 2008]

FZD8 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22102907).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD8	NM_031866.3 linkuse as main transcript	c.2039C>G	p.Ala680Gly	missense_variant	1/1	ENST00000374694.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD8	ENST00000374694.3 linkuse as main transcript	c.2039C>G	p.Ala680Gly	missense_variant	1/1		NM_031866.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000413

AC:

AN:

145394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000153

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000603

AC:

AN:

1327200

Hom.:

Cov.:

AF XY:

0.00000455

AC XY:

AN XY:

658674

show subpopulations

Gnomad4 AFR exome

AF:

0.000251

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.65e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000413

AC:

AN:

145394

Hom.:

Cov.:

AF XY:

0.0000567

AC XY:

AN XY:

70534

show subpopulations

Gnomad4 AFR

AF:

0.000153

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000480

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.2039C>G (p.A680G) alteration is located in exon 1 (coding exon 1) of the FZD8 gene. This alteration results from a C to G substitution at nucleotide position 2039, causing the alanine (A) at amino acid position 680 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.022

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.64

REVEL

Benign

0.21

Sift

Benign

0.17

Sift4G

Benign

0.37

Polyphen

0.0050

Vest4

0.23

MutPred

0.17

Gain of phosphorylation at S681 (P = 0.1362);

MVP

0.69

ClinPred

0.43

GERP RS

3.3

Varity_R

0.11

gMVP

0.25

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