8-28527195-A-T

Variant names:

• chr8-28527195-A-T
• rs2241802
• NM_017412.4:c.435A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017412.4(FZD3):​c.435A>T​(p.Leu145Phe) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L145S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: FZD3 NM_017412.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250
• Publications: 37 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13817134).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017412.4. 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
	FZD3	NM_017412.4	MANE Select	c.435A>T	p.Leu145Phe	missense	Exon 5 of 8	NP_059108.1
	FZD3	NM_001412909.1		c.-139A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 7	NP_001399838.1
	FZD3	NM_001412910.1		c.-139A>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 8	NP_001399839.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD3	ENST00000240093.8	TSL:1 MANE Select	c.435A>T	p.Leu145Phe	missense	Exon 5 of 8	ENSP00000240093.3
	FZD3	ENST00000537916.2	TSL:2	c.435A>T	p.Leu145Phe	missense	Exon 4 of 7	ENSP00000437489.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.25
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.13
Sift	Benign	0.72	T
Sift4G	Benign	0.70	T
Polyphen		0.023	B
Vest4		0.26
MutPred		0.32		Gain of sheet (P = 0.0344)
MVP		0.60
MPC		0.74
ClinPred		0.050	T
GERP RS		2.4
Varity_R		0.033
gMVP		0.47
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs2241802; hg19: chr8-28384712;