8-103300204-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003506.4(FZD6):c.97A>T(p.Met33Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M33V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FZD6 NM_003506.4 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10744271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD6	NM_003506.4	c.97A>T	p.Met33Leu	missense_variant	2/7	ENST00000358755.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD6	ENST00000358755.5	c.97A>T	p.Met33Leu	missense_variant	2/7	1	NM_003506.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	9.0
Dann	Benign	0.84
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.64	N;N;.
MutationTaster	Benign	0.94	P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.54	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.12
MutPred		0.28		Loss of catalytic residue at V29 (P = 0.1072);Loss of catalytic residue at V29 (P = 0.1072);.;
MVP		0.59
MPC		0.24
ClinPred		0.12	T
GERP RS		-0.68
Varity_R		0.083
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;