chr8-103300204-A-G

Position:

• chr8-103300204-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_001164616.2(FZD6):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,606,408 control chromosomes in the GnomAD database, including 50,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4285 hom., cov: 31)
  • Exomes 𝑓: 0.25 (45822 hom.)
• Consequence: FZD6 NM_001164616.2 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0290

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 8-103300204-A-G is Benign according to our data. Variant chr8-103300204-A-G is described in ClinVar as [Benign]. Clinvar id is 1285287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD6	NM_003506.4	c.97A>G	p.Met33Val	missense_variant	2/7	ENST00000358755.5	NP_003497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD6	ENST00000358755.5	c.97A>G	p.Met33Val	missense_variant	2/7	1	NM_003506.4	ENSP00000351605.4

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35134 AN: 151962 Hom.: 4289 Cov.: 31

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.248

GnomAD3 exomes AF: 0.217 AC: 54480 AN: 251446 Hom.: 6794 AF XY: 0.223 AC XY: 30316 AN XY: 135894

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.00739

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.245 AC: 356430 AN: 1454328 Hom.: 45822 Cov.: 30 AF XY: 0.245 AC XY: 177311 AN XY: 724002

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.00512

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.261

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.231 AC: 35156 AN: 152080 Hom.: 4285 Cov.: 31 AF XY: 0.227 AC XY: 16886 AN XY: 74350

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.245

Alfa AF: 0.258 Hom.: 10751

Bravo AF: 0.227

TwinsUK AF: 0.259 AC: 960

ALSPAC AF: 0.243 AC: 938

ESP6500AA AF: 0.211 AC: 930

ESP6500EA AF: 0.265 AC: 2279

ExAC AF: 0.224 AC: 27155

Asia WGS AF: 0.101 AC: 353 AN: 3478

EpiCase AF: 0.275

EpiControl AF: 0.277

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Nonsyndromic congenital nail disorder 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.7
DANN	Benign	0.88
DEOGEN2	Benign	0.20	T;T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.61	.;T;D
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N;N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.54	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.039
MPC		0.26
ClinPred		0.00048	T
GERP RS		-0.68
Varity_R		0.080
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs827528; hg19: chr8-104312432; COSMIC: COSV62470878; COSMIC: COSV62470878;