7-73434150-G-T

Variant names:

• chr7-73434150-G-T
• rs782497063
• NM_003508.3:c.143G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003508.3(FZD9):​c.143G>T​(p.Arg48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,400,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R48H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FZD9 NM_003508.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.661
• Publications: 0 publications found

Genes affected

FZD9 (HGNC:4047): (frizzled class receptor 9) Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD9 gene is located within the Williams syndrome common deletion region of chromosome 7, and heterozygous deletion of the FZD9 gene may contribute to the Williams syndrome phenotype. FZD9 is expressed predominantly in brain, testis, eye, skeletal muscle, and kidney. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35773304).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003508.3. 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
	FZD9	NM_003508.3	MANE Select	c.143G>T	p.Arg48Leu	missense	Exon 1 of 1	NP_003499.1	O00144

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD9	ENST00000344575.5	TSL:6 MANE Select	c.143G>T	p.Arg48Leu	missense	Exon 1 of 1	ENSP00000345785.3	O00144

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400900 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 696222

⚠️ 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: 29394

American (AMR) AF: 0.00 AC: 0 AN: 38952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24284

East Asian (EAS) AF: 0.00 AC: 0 AN: 34828

South Asian (SAS) AF: 0.00 AC: 0 AN: 79806

European-Finnish (FIN) AF: 0.0000244 AC: 1 AN: 40974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4856

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089738

Other (OTH) AF: 0.00 AC: 0 AN: 58068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.66
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.065	T
Polyphen		0.17	B
Vest4		0.31
MutPred		0.51		Loss of MoRF binding (P = 0.1014)
MVP		0.28
ClinPred		0.79	D
GERP RS		1.7
PromoterAI		0.0066	Neutral
Varity_R		0.31
gMVP		0.55
Mutation Taster		=69/31	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: rs782497063; hg19: chr7-72848480;