8-28555908-C-G

Position:

• chr8-28555908-C-G

Variant summary

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

The NM_017412.4(FZD3):​c.1724C>G​(p.Ala575Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FZD3 NM_017412.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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=0.31362328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD3	NM_017412.4	c.1724C>G	p.Ala575Gly	missense_variant	7/8	ENST00000240093.8	NP_059108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD3	ENST00000240093.8	c.1724C>G	p.Ala575Gly	missense_variant	7/8	1	NM_017412.4	ENSP00000240093	P1
FZD3	ENST00000537916.2	c.1724C>G	p.Ala575Gly	missense_variant	6/7	2		ENSP00000437489	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 12, 2024

The c.1724C>G (p.A575G) alteration is located in exon 7 (coding exon 5) of the FZD3 gene. This alteration results from a C to G substitution at nucleotide position 1724, causing the alanine (A) at amino acid position 575 to be replaced by a glycine (G). 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	0.093
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;.
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.11	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.76	P;P
Vest4		0.30
MutPred		0.10		Loss of MoRF binding (P = 0.1079);Loss of MoRF binding (P = 0.1079);
MVP		0.92
MPC		0.63
ClinPred		0.84	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-28413425;