chr8-103331379-C-A

Variant names:

• chr8-103331379-C-A
• rs12549394
• NM_003506.4:c.1991C>A

Variant summary

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

• 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
• Publications: 14 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=0.0021431744).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD6	NM_003506.4	MANE Select	c.1991C>A	p.Ala664Glu	missense	Exon 7 of 7	NP_003497.2
	FZD6	NM_001164615.2		c.1991C>A	p.Ala664Glu	missense	Exon 7 of 7	NP_001158087.1
	FZD6	NM_001164616.2		c.1895C>A	p.Ala632Glu	missense	Exon 8 of 8	NP_001158088.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD6	ENST00000358755.5	TSL:1 MANE Select	c.1991C>A	p.Ala664Glu	missense	Exon 7 of 7	ENSP00000351605.4
	FZD6	ENST00000522566.5	TSL:1	c.1991C>A	p.Ala664Glu	missense	Exon 7 of 7	ENSP00000429055.1
	FZD6	ENST00000522484.5	TSL:1	n.*438C>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000428301.1

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

GnomAD2 exomes AF: 0.0135 AC: 3396 AN: 251476 AF XY: 0.0108

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 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

African (AFR) AF: 0.00105 AC: 35 AN: 33452

American (AMR) AF: 0.0801 AC: 3584 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0245 AC: 972 AN: 39684

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.0000801 AC: 89 AN: 1110548

Other (OTH) AF: 0.00340 AC: 205 AN: 60342

GnomAD4 genome AF: 0.00731 AC: 1112 AN: 152208 Hom.: 39 Cov.: 32 AF XY: 0.00829 AC XY: 617 AN XY: 74426

African (AFR) AF: 0.00202 AC: 84 AN: 41540

American (AMR) AF: 0.0576 AC: 881 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68010

Other (OTH) AF: 0.0105 AC: 22 AN: 2104

Alfa AF: 0.00244 Hom.: 11

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 v4.9

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
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.38
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.20
Sift	Uncertain	0.019	D
Sift4G	Benign	0.33	T
Polyphen		0.012	B
Vest4		0.065
MPC		0.31
ClinPred		0.0018	T
GERP RS		-8.1
Varity_R		0.076
gMVP		0.23
Mutation Taster		=100/0	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: rs12549394; hg19: chr8-104343607;