22-28883835-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001206998.2(ZNRF3):c.69C>G(p.Pro23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 979,426 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 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: ZNRF3 NM_001206998.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.315

Genes affected

ZNRF3 (HGNC:18126): (zinc and ring finger 3) Enables frizzled binding activity and ubiquitin-protein transferase activity. Involved in cellular protein metabolic process and negative regulation of Wnt signaling pathway. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 22-28883835-C-G is Benign according to our data. Variant chr22-28883835-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2653039.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.315 with no splicing effect.
• BS2: High AC in GnomAd at 156 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNRF3	NM_001206998.2	c.69C>G	p.Pro23=	synonymous_variant	1/9	ENST00000544604.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNRF3	ENST00000544604.7	c.69C>G	p.Pro23=	synonymous_variant	1/9	1	NM_001206998.2	A2

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 156 AN: 145452 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00314

Gnomad FIN AF: 0.00498

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000995

GnomAD4 exome AF: 0.000307 AC: 256 AN: 833926 Hom.: 1 Cov.: 33 AF XY: 0.000296 AC XY: 114 AN XY: 385180

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00525

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000198

Gnomad4 OTH exome AF: 0.000476

GnomAD4 genome AF: 0.00107 AC: 156 AN: 145500 Hom.: 1 Cov.: 32 AF XY: 0.00120 AC XY: 85 AN XY: 70770

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000204

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00315

Gnomad4 FIN AF: 0.00498

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000986

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.000351

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

ZNRF3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	9.9
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1025350681; hg19: chr22-29279823;