rs80358282

chr11-86954881-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 2P and 18B. PM1 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_012193.4(FZD4):c.205C>T(p.His69Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000314 in 1,613,404 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: FZD4 NM_012193.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.85

Genes affected

FZD4 (HGNC:4042): (frizzled class receptor 4) This 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. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. This protein may play a role as a positive regulator of the Wingless type MMTV integration site signaling pathway. A transcript variant retaining intronic sequence and encoding a shorter isoform has been described, however, its expression is not supported by other experimental evidence. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• PM1: In a disulfide_bond (size 61) in uniprot entity FZD4_HUMAN there are 35 pathogenic changes around while only 2 benign (95%) in NM_012193.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.10089463).
• BP6: Variant 11-86954881-G-A is Benign according to our data. Variant chr11-86954881-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86954881-G-A is described in Lovd as [Likely_benign]. Variant chr11-86954881-G-A is described in Lovd as [Pathogenic]. Variant chr11-86954881-G-A is described in Lovd as [Pathogenic]. Variant chr11-86954881-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000323 (472/1461182) while in subpopulation EAS AF= 0.00703 (279/39684). AF 95% confidence interval is 0.00635. There are 2 homozygotes in gnomad4_exome. There are 237 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 34 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD4	NM_012193.4	c.205C>T	p.His69Tyr	missense_variant	1/2	ENST00000531380.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD4	ENST00000531380.2	c.205C>T	p.His69Tyr	missense_variant	1/2	1	NM_012193.4	P1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00369

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000520 AC: 128 AN: 246338 Hom.: 0 AF XY: 0.000515 AC XY: 69 AN XY: 133980

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00428

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000323 AC: 472 AN: 1461182 Hom.: 2 Cov.: 33 AF XY: 0.000326 AC XY: 237 AN XY: 726918

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00703

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000189

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00370

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000286 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000528 AC: 64

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -

Exudative vitreoretinopathy 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.20	B
Vest4		0.82
MVP		0.74
MPC		1.0
ClinPred		0.16	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.92
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80358282; hg19: chr11-86665923;