rs827528

Variant names:

• chr8-103300204-A-G
• rs827528
• NM_003506.4:c.97A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-103300204-A-G
• chr8-103300204-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003506.4(FZD6):​c.97A>G​(p.Met33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,606,408 control chromosomes in the GnomAD database, including 50,107 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4285 hom., cov: 31)
  • Exomes 𝑓: 0.25 (45822 hom.)
• Consequence: FZD6 NM_003506.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0290
• Publications: 37 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047037303).
• BP6: Variant 8-103300204-A-G is Benign according to our data. Variant chr8-103300204-A-G is described in ClinVar as Benign. ClinVar VariationId is 1285287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.26 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.97A>G	p.Met33Val	missense	Exon 2 of 7	NP_003497.2
	FZD6	NM_001164616.2		c.1A>G	p.Met1?	start_lost	Exon 3 of 8	NP_001158088.1
	FZD6	NM_001164615.2		c.97A>G	p.Met33Val	missense	Exon 2 of 7	NP_001158087.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD6	ENST00000358755.5	TSL:1 MANE Select	c.97A>G	p.Met33Val	missense	Exon 2 of 7	ENSP00000351605.4
	FZD6	ENST00000522566.5	TSL:1	c.97A>G	p.Met33Val	missense	Exon 2 of 7	ENSP00000429055.1
	FZD6	ENST00000522484.5	TSL:1	n.97A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000428301.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35134 AN: 151962 Hom.: 4289 Cov.: 31

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.248

GnomAD2 exomes AF: 0.217 AC: 54480 AN: 251446 AF XY: 0.223

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.00739

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.245 AC: 356430 AN: 1454328 Hom.: 45822 Cov.: 30 AF XY: 0.245 AC XY: 177311 AN XY: 724002

African (AFR) AF: 0.222 AC: 7400 AN: 33344

American (AMR) AF: 0.134 AC: 5978 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8420 AN: 26076

East Asian (EAS) AF: 0.00512 AC: 203 AN: 39658

South Asian (SAS) AF: 0.201 AC: 17287 AN: 86122

European-Finnish (FIN) AF: 0.233 AC: 12453 AN: 53416

Middle Eastern (MID) AF: 0.327 AC: 1878 AN: 5746

European-Non Finnish (NFE) AF: 0.261 AC: 288094 AN: 1105108

Other (OTH) AF: 0.245 AC: 14717 AN: 60138

GnomAD4 genome AF: 0.231 AC: 35156 AN: 152080 Hom.: 4285 Cov.: 31 AF XY: 0.227 AC XY: 16886 AN XY: 74350

African (AFR) AF: 0.217 AC: 9013 AN: 41476

American (AMR) AF: 0.184 AC: 2808 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1142 AN: 3470

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5188

South Asian (SAS) AF: 0.186 AC: 895 AN: 4816

European-Finnish (FIN) AF: 0.224 AC: 2359 AN: 10552

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.263 AC: 17876 AN: 67980

Other (OTH) AF: 0.245 AC: 518 AN: 2110

Alfa AF: 0.253 Hom.: 20756

Bravo AF: 0.227

TwinsUK AF: 0.259 AC: 960

ALSPAC AF: 0.243 AC: 938

ESP6500AA AF: 0.211 AC: 930

ESP6500EA AF: 0.265 AC: 2279

ExAC AF: 0.224 AC: 27155

Asia WGS AF: 0.101 AC: 353 AN: 3478

EpiCase AF: 0.275

EpiControl AF: 0.277

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nonsyndromic congenital nail disorder 1 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.7
DANN	Benign	0.88
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N
PhyloP100		0.029
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.11
Sift	Benign	0.19	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.26
ClinPred		0.00048	T
GERP RS		-0.68
Varity_R		0.080
gMVP		0.58
Mutation Taster		=168/32	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs827528; hg19: chr8-104312432; COSMIC: COSV62470878; COSMIC: COSV62470878;