rs1223920489

Variant names:

• chr17-44558988-G-A
• rs1223920489
• NM_001466.4:c.1300G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-44558988-G-A
• chr17-44558988-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001466.4(FZD2):​c.1300G>A​(p.Gly434Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G434V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FZD2 NM_001466.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.99
• Publications: 3 publications found

Genes affected

FZD2 (HGNC:4040): (frizzled class receptor 2) This intronless 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. This gene encodes a protein that is coupled to the beta-catenin canonical signaling pathway. Competition between the wingless-type MMTV integration site family, member 3A and wingless-type MMTV integration site family, member 5A gene products for binding of this protein is thought to regulate the beta-catenin-dependent and -independent pathways. [provided by RefSeq, Dec 2010]

FZD2 Gene-Disease associations (from GenCC):

• autosomal dominant omodysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant Robinow syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a transmembrane_region Helical; Name=5 (size 20) in uniprot entity FZD2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001466.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44558989-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 488050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 17-44558988-G-A is Pathogenic according to our data. Variant chr17-44558988-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 488061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD2	NM_001466.4	c.1300G>A	p.Gly434Ser	missense_variant	Exon 1 of 1	ENST00000315323.5	NP_001457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD2	ENST00000315323.5	c.1300G>A	p.Gly434Ser	missense_variant	Exon 1 of 1	6	NM_001466.4	ENSP00000323901.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251294 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Robinow syndrome 1 Pathogenic:1

Dec 07, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Dec 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36867021, 35047859, 29276006, 31231135) -

Autosomal dominant Robinow syndrome 2 Pathogenic:1

Jun 01, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.84		Loss of stability (P = 0.0439);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.94
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1223920489; hg19: chr17-42636356;