8-103300153-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (25 hom.)
• Consequence: FZD6 NM_003506.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.14

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]

ACMG classification

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD6	NM_003506.4	c.46C>G	p.Leu16Val	missense_variant	2/7	ENST00000358755.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD6	ENST00000358755.5	c.46C>G	p.Leu16Val	missense_variant	2/7	1	NM_003506.4	P1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152124 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00306 AC: 769 AN: 251448 Hom.: 4 AF XY: 0.00302 AC XY: 410 AN XY: 135906

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 SAS exome AF: 0.000163

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.: 25 Cov.: 28 AF XY: 0.00474 AC XY: 3420 AN XY: 722144

Gnomad4 AFR exome AF: 0.000541

Gnomad4 AMR exome AF: 0.000828

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00602

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74440

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00424 Hom.: 1

Bravo AF: 0.00305

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00358 AC: 434

EpiCase AF: 0.00458

EpiControl AF: 0.00522

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FZD6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

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	T
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	N
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.64	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
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	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.33

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

Other links and lift over

dbSNP: rs117477069; hg19: chr8-104312381; COSMIC: COSV62471143; COSMIC: COSV62471143;