8-28520718-G-A

Position:

• chr8-28520718-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017412.4(FZD3):​c.270G>A​(p.Met90Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FZD3 NM_017412.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

FZD3 (HGNC:4041): (frizzled class receptor 3) This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. The function of this protein is unknown, although it may play a role in mammalian hair follicle development. Alternative splicing results in multiple transcript variants. This gene is a susceptibility locus for schizophrenia. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2678525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD3	NM_017412.4	c.270G>A	p.Met90Ile	missense_variant	4/8	ENST00000240093.8	NP_059108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD3	ENST00000240093.8	c.270G>A	p.Met90Ile	missense_variant	4/8	1	NM_017412.4	ENSP00000240093.3
FZD3	ENST00000537916.2	c.270G>A	p.Met90Ile	missense_variant	3/7	2		ENSP00000437489.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459898 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726290

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.270G>A (p.M90I) alteration is located in exon 4 (coding exon 2) of the FZD3 gene. This alteration results from a G to A substitution at nucleotide position 270, causing the methionine (M) at amino acid position 90 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.40	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.24
Sift	Benign	0.093	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0010	B;B
Vest4		0.44
MutPred		0.66		Loss of catalytic residue at M90 (P = 0.288);Loss of catalytic residue at M90 (P = 0.288);
MVP		0.69
MPC		0.69
ClinPred		0.57	D
GERP RS		5.6
Varity_R		0.25
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs746607374; hg19: chr8-28378235;