rs80216383

chr8-103324524-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_003506.4(FZD6):c.418C>T(p.His140Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,609,776 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (8 hom.)
• Consequence: FZD6 NM_003506.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10

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 Likely_benign. Variant got -5 ACMG points.

• PP5: Variant 8-103324524-C-T is Pathogenic according to our data. Variant chr8-103324524-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.004542291).. Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0063 (959/152256) while in subpopulation AFR AF= 0.0214 (891/41552). AF 95% confidence interval is 0.0203. There are 8 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD6	NM_003506.4	c.418C>T	p.His140Tyr	missense_variant	4/7	ENST00000358755.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD6	ENST00000358755.5	c.418C>T	p.His140Tyr	missense_variant	4/7	1	NM_003506.4	P1

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 957 AN: 152138 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00164 AC: 412 AN: 251116 Hom.: 4 AF XY: 0.00120 AC XY: 163 AN XY: 135738

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.00104

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: 0.0000792

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000676 AC: 985 AN: 1457520 Hom.: 8 Cov.: 30 AF XY: 0.000601 AC XY: 436 AN XY: 725478

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000496

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00630 AC: 959 AN: 152256 Hom.: 8 Cov.: 33 AF XY: 0.00619 AC XY: 461 AN XY: 74426

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00205 Hom.: 3

Bravo AF: 0.00710

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.090
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.46	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.038	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		0.21	B;B;.
Vest4		0.12
MVP		0.84
MPC		0.33
ClinPred		0.018	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs80216383; hg19: chr8-104336752;