NM_003506.4:c.418C>T

Variant names:

• chr8-103324524-C-T
• rs80216383
• NM_003506.4:c.418C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 4 publications found

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]

BAALC-AS1 (HGNC:50461): (BAALC antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004542291).
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003506.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD6	NM_003506.4	MANE Select	c.418C>T	p.His140Tyr	missense	Exon 4 of 7	NP_003497.2
	FZD6	NM_001164615.2		c.418C>T	p.His140Tyr	missense	Exon 4 of 7	NP_001158087.1	O60353-1
	FZD6	NM_001164616.2		c.322C>T	p.His108Tyr	missense	Exon 5 of 8	NP_001158088.1	O60353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD6	ENST00000358755.5	TSL:1 MANE Select	c.418C>T	p.His140Tyr	missense	Exon 4 of 7	ENSP00000351605.4	O60353-1
	FZD6	ENST00000522566.5	TSL:1	c.418C>T	p.His140Tyr	missense	Exon 4 of 7	ENSP00000429055.1	O60353-1
	FZD6	ENST00000522484.5	TSL:1	n.418C>T		non_coding_transcript_exon	Exon 4 of 6	ENSP00000428301.1	G5EA13

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

GnomAD2 exomes AF: 0.00164 AC: 412 AN: 251116 AF XY: 0.00120

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 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

African (AFR) AF: 0.0233 AC: 776 AN: 33358

American (AMR) AF: 0.00139 AC: 62 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.0000496 AC: 55 AN: 1108160

Other (OTH) AF: 0.00138 AC: 83 AN: 60226

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

African (AFR) AF: 0.0214 AC: 891 AN: 41552

American (AMR) AF: 0.00334 AC: 51 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00332 Hom.: 7

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 v4.9

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
Eigen	Benign	-0.090
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.18
Sift	Benign	0.038	D
Sift4G	Uncertain	0.046	D
Polyphen		0.21	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs80216383; hg19: chr8-104336752;