chr8-28527871-T-G

Position:

• chr8-28527871-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017412.4(FZD3):​c.1111T>G​(p.Leu371Val) 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 pathogenic 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: 0.819

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD3	NM_017412.4	c.1111T>G	p.Leu371Val	missense_variant	5/8	ENST00000240093.8	NP_059108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD3	ENST00000240093.8	c.1111T>G	p.Leu371Val	missense_variant	5/8	1	NM_017412.4	ENSP00000240093	P1
FZD3	ENST00000537916.2	c.1111T>G	p.Leu371Val	missense_variant	4/7	2		ENSP00000437489	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Jun 10, 2024

The c.1111T>G (p.L371V) alteration is located in exon 5 (coding exon 3) of the FZD3 gene. This alteration results from a T to G substitution at nucleotide position 1111, causing the leucine (L) at amino acid position 371 to be replaced by a valine (V). 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.050	D;D
Sift4G	Uncertain	0.059	T;T
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.80		Gain of catalytic residue at L371 (P = 0.0076);Gain of catalytic residue at L371 (P = 0.0076);
MVP		0.90
MPC		1.6
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.21
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-28385388;