12-130163484-C-A

Variant names:

• chr12-130163484-C-A
• rs765524304
• NM_007197.4:c.542C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007197.4(FZD10):​c.542C>A​(p.Pro181Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. P181R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FZD10 NM_007197.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.362
• Publications: 0 publications found

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]

FZD10-AS1 (HGNC:48632): (FZD10 antisense divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060170233).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007197.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD10	NM_007197.4	MANE Select	c.542C>A	p.Pro181Gln	missense	Exon 1 of 1	NP_009128.1	Q9ULW2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD10	ENST00000229030.5	TSL:6 MANE Select	c.542C>A	p.Pro181Gln	missense	Exon 1 of 1	ENSP00000229030.4	Q9ULW2
	FZD10	ENST00000539839.1	TSL:6	c.444C>A	p.Pro148Pro	synonymous	Exon 1 of 1	ENSP00000438460.1	F5H450
	FZD10-AS1	ENST00000815564.1		n.12G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448738 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 719624

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32958

American (AMR) AF: 0.00 AC: 0 AN: 43000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25366

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.00 AC: 0 AN: 85284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105806

Other (OTH) AF: 0.00 AC: 0 AN: 59678

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.4
DANN	Benign	0.92
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.36
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.15
Sift	Benign	0.083	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.055
MutPred		0.20		Loss of glycosylation at P181 (P = 0.0988)
MVP		0.061
ClinPred		0.076	T
GERP RS		-8.3
Varity_R		0.038
gMVP		0.44
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: rs765524304; hg19: chr12-130648029;