7-73434428-C-T

Variant names:

• chr7-73434428-C-T
• rs782047303
• NM_003508.3:c.421C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003508.3(FZD9):​c.421C>T​(p.Arg141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,405,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: FZD9 NM_003508.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD9	NM_003508.3	c.421C>T	p.Arg141Trp	missense_variant	Exon 1 of 1	ENST00000344575.5	NP_003499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD9	ENST00000344575.5	c.421C>T	p.Arg141Trp	missense_variant	Exon 1 of 1	6	NM_003508.3	ENSP00000345785.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000114 AC: 16 AN: 1405266 Hom.: 0 Cov.: 33 AF XY: 0.0000129 AC XY: 9 AN XY: 697500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000550

Gnomad4 SAS exome AF: 0.0000625

Gnomad4 FIN exome AF: 0.0000260

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.0000856

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000175 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.421C>T (p.R141W) alteration is located in exon 1 (coding exon 1) of the FZD9 gene. This alteration results from a C to T substitution at nucleotide position 421, causing the arginine (R) at amino acid position 141 to be replaced by a tryptophan (W). 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	0.38
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.57		Loss of disorder (P = 0.0049);
MVP		0.72
ClinPred		0.77	D
GERP RS		2.3
Varity_R		0.37
gMVP		0.62

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: rs782047303; hg19: chr7-72848758;