12-130163320-C-A

Variant names:

• chr12-130163320-C-A
• rs777449665
• NM_007197.4:c.378C>A

Variant summary

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

The NM_007197.4(FZD10):​c.378C>A​(p.Phe126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FZD10 NM_007197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

FZD10 (HGNC:4039): (frizzled class receptor 10) This gene is a member of the frizzled gene family. Members of this family encode 7-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. Using array analysis, expression of this intronless gene is significantly up-regulated in two cases of primary colon cancer. [provided by RefSeq, Jul 2008]

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, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD10	NM_007197.4	c.378C>A	p.Phe126Leu	missense_variant	Exon 1 of 1	ENST00000229030.5	NP_009128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD10	ENST00000229030.5	c.378C>A	p.Phe126Leu	missense_variant	Exon 1 of 1	6	NM_007197.4	ENSP00000229030.4
FZD10	ENST00000539839.1	c.280C>A	p.Gln94Lys	missense_variant	Exon 1 of 1	6		ENSP00000438460.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250548 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460882 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 726758

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.378C>A (p.F126L) alteration is located in exon 1 (coding exon 1) of the FZD10 gene. This alteration results from a C to A substitution at nucleotide position 378, causing the phenylalanine (F) at amino acid position 126 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.86	P
Vest4		0.64
MutPred		0.70		Gain of catalytic residue at F126 (P = 0.0222);
MVP		0.37
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.69

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

Other links and lift over

dbSNP: rs777449665; hg19: chr12-130647865; COSMIC: COSV57475090; COSMIC: COSV57475090;