22-28904318-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206998.2(ZNRF3):c.300+20252C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 152,168 control chromosomes in the GnomAD database, including 1,933 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1933 hom., cov: 32)
• Consequence: ZNRF3 NM_001206998.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNRF3	NM_001206998.2	c.300+20252C>T		intron_variant		ENST00000544604.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNRF3	ENST00000544604.7	c.300+20252C>T		intron_variant		1	NM_001206998.2	A2

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20565 AN: 152052 Hom.: 1932 Cov.: 32

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.167

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.135 AC: 20559 AN: 152168 Hom.: 1933 Cov.: 32 AF XY: 0.138 AC XY: 10233 AN XY: 74388

Gnomad4 AFR AF: 0.0422

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.153

Gnomad4 OTH AF: 0.164

Alfa AF: 0.160 Hom.: 3392

Bravo AF: 0.132

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs16986825; hg19: chr22-29300306;