dbSNP rs780099524: FZD6:p.His60Asp (chr8-103318590-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003506.4(FZD6):c.178C>G(p.His60Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000141 in 1,418,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FZD6
NM_003506.4 missense, splice_region

Scores

Splicing: ADA: 0.001559

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.73

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27699375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD6	NM_003506.4 link	c.178C>G	p.His60Asp	missense_variant, splice_region_variant	Exon 3 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.178C>G	p.His60Asp	missense_variant, splice_region_variant	Exon 3 of 7	1	NM_003506.4	ENSP00000351605.4		O60353-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250774

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1418706

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

708626

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.016

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

.;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.32

N;N;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.25

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.079

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.37

MutPred

0.49

Loss of catalytic residue at L62 (P = 0.0556);Loss of catalytic residue at L62 (P = 0.0556);.;

MVP

0.92

MPC

0.35

ClinPred

0.35

GERP RS

3.9

Varity_R

0.12

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.19

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