8-103325139-A-C

Variant names:

• chr8-103325139-A-C
• rs3808553
• NM_003506.4:c.1033A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003506.4(FZD6):​c.1033A>C​(p.Met345Leu) variant causes a missense change. The variant allele was found at a frequency of 0.462 in 1,613,692 control chromosomes in the GnomAD database, including 175,358 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.43 (14562 hom., cov: 32)
  • Exomes 𝑓: 0.47 (160796 hom.)
• Consequence: FZD6 NM_003506.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79
• Publications: 41 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=5.156825E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD6	NM_003506.4	c.1033A>C	p.Met345Leu	missense_variant	Exon 4 of 7	ENST00000358755.5	NP_003497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD6	ENST00000358755.5	c.1033A>C	p.Met345Leu	missense_variant	Exon 4 of 7	1	NM_003506.4	ENSP00000351605.4

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65135 AN: 151916 Hom.: 14553 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.472 AC: 118587 AN: 251410 AF XY: 0.465

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.597

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.627

Gnomad FIN exome AF: 0.443

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.465 AC: 680381 AN: 1461658 Hom.: 160796 Cov.: 45 AF XY: 0.464 AC XY: 337391 AN XY: 727154

African (AFR) AF: 0.305 AC: 10199 AN: 33480

American (AMR) AF: 0.586 AC: 26184 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9488 AN: 26132

East Asian (EAS) AF: 0.620 AC: 24623 AN: 39696

South Asian (SAS) AF: 0.450 AC: 38792 AN: 86252

European-Finnish (FIN) AF: 0.439 AC: 23469 AN: 53414

Middle Eastern (MID) AF: 0.410 AC: 2366 AN: 5768

European-Non Finnish (NFE) AF: 0.465 AC: 517497 AN: 1111810

Other (OTH) AF: 0.460 AC: 27763 AN: 60388

GnomAD4 genome AF: 0.429 AC: 65170 AN: 152034 Hom.: 14562 Cov.: 32 AF XY: 0.429 AC XY: 31906 AN XY: 74290

African (AFR) AF: 0.309 AC: 12824 AN: 41466

American (AMR) AF: 0.523 AC: 7992 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1262 AN: 3466

East Asian (EAS) AF: 0.614 AC: 3176 AN: 5170

South Asian (SAS) AF: 0.439 AC: 2115 AN: 4816

European-Finnish (FIN) AF: 0.443 AC: 4677 AN: 10560

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31822 AN: 67958

Other (OTH) AF: 0.434 AC: 916 AN: 2110

Alfa AF: 0.448 Hom.: 53307

Bravo AF: 0.428

TwinsUK AF: 0.473 AC: 1753

ALSPAC AF: 0.475 AC: 1829

ESP6500AA AF: 0.304 AC: 1341

ESP6500EA AF: 0.466 AC: 4010

ExAC AF: 0.462 AC: 56141

Asia WGS AF: 0.539 AC: 1873 AN: 3478

EpiCase AF: 0.447

EpiControl AF: 0.448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.30	T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.71	.;T;T
MetaRNN	Benign	0.000052	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.075	N;N;.
PhyloP100		3.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.0080	B;B;.
Vest4		0.10
MutPred		0.22		Loss of methylation at K347 (P = 0.097);Loss of methylation at K347 (P = 0.097);.;
MPC		0.26
ClinPred		0.040	T
GERP RS		6.2
Varity_R		0.28
gMVP		0.36
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3808553; hg19: chr8-104337367; COSMIC: COSV62470797;