chr8-103300153-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003506.4(FZD6):ā€‹c.46C>Gā€‹(p.Leu16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,602,314 control chromosomes in the GnomAD database, including 25 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 Likely benign (no stars).

Frequency

Genomes: š‘“ 0.0030 ( 0 hom., cov: 32)
Exomes š‘“: 0.0048 ( 25 hom. )

Consequence

FZD6
NM_003506.4 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.14
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0041077137).
BP6
Variant 8-103300153-C-G is Benign according to our data. Variant chr8-103300153-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3039484.Status of the report is no_assertion_criteria_provided, 0 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.003 (457/152242) while in subpopulation NFE AF= 0.00526 (358/68012). AF 95% confidence interval is 0.00481. There are 0 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FZD6NM_003506.4 linkuse as main transcriptc.46C>G p.Leu16Val missense_variant 2/7 ENST00000358755.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FZD6ENST00000358755.5 linkuse as main transcriptc.46C>G p.Leu16Val missense_variant 2/71 NM_003506.4 P1O60353-1

Frequencies

GnomAD3 genomes
AF:
0.00300
AC:
457
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000966
Gnomad AMI
AF:
0.0330
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00526
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00306
AC:
769
AN:
251448
Hom.:
4
AF XY:
0.00302
AC XY:
410
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000738
Gnomad AMR exome
AF:
0.000781
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00125
Gnomad NFE exome
AF:
0.00602
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.00479
AC:
6949
AN:
1450072
Hom.:
25
Cov.:
28
AF XY:
0.00474
AC XY:
3420
AN XY:
722144
show subpopulations
Gnomad4 AFR exome
AF:
0.000541
Gnomad4 AMR exome
AF:
0.000828
Gnomad4 ASJ exome
AF:
0.000230
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000174
Gnomad4 FIN exome
AF:
0.00152
Gnomad4 NFE exome
AF:
0.00602
Gnomad4 OTH exome
AF:
0.00280
GnomAD4 genome
AF:
0.00300
AC:
457
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.00271
AC XY:
202
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.000963
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.00526
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00424
Hom.:
1
Bravo
AF:
0.00305
TwinsUK
AF:
0.00809
AC:
30
ALSPAC
AF:
0.00467
AC:
18
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00512
AC:
44
ExAC
AF:
0.00358
AC:
434
EpiCase
AF:
0.00458
EpiControl
AF:
0.00522

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

FZD6-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 13, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.058
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
0.0020
DANN
Benign
0.54
DEOGEN2
Benign
0.14
T;T
Eigen
Benign
-2.4
Eigen_PC
Benign
-2.4
FATHMM_MKL
Benign
0.014
N
LIST_S2
Benign
0.039
.;T
M_CAP
Benign
0.070
D
MetaRNN
Benign
0.0041
T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
-0.64
N;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.58
N;N
REVEL
Benign
0.20
Sift
Benign
0.80
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;B
Vest4
0.018
MVP
0.52
MPC
0.26
ClinPred
0.0023
T
GERP RS
-11
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.034
gMVP
0.33

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs117477069; hg19: chr8-104312381; COSMIC: COSV62471143; COSMIC: COSV62471143; API