rs12549394

chr8-103331379-C-Achr8-103331379-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0073 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (183 hom.)
• Consequence: FZD6 NM_003506.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.384

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 -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/exons	MANE	UniProt
FZD6	NM_003506.4	c.1991C>A	p.Ala664Glu	missense_variant	7/7	ENST00000358755.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD6	ENST00000358755.5	c.1991C>A	p.Ala664Glu	missense_variant	7/7	1	NM_003506.4	P1

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1115 AN: 152090 Hom.: 39 Cov.: 32

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

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.: 29 AF XY: 0.00298 AC XY: 2163 AN XY: 726544

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.: 39 Cov.: 32 AF XY: 0.00829 AC XY: 617 AN XY: 74426

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.: 7

Bravo AF: 0.0116

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0103 AC: 1245

Asia WGS AF: 0.0110 AC: 39 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	T
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	N
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.21	T
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	T
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

Other links and lift over

dbSNP: rs12549394; hg19: chr8-104343607;