22-28904318-C-T

Variant names:

• chr22-28904318-C-T
• rs16986825
• NM_001206998.2:c.300+20252C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 45 publications found

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]

ZNRF3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206998.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNRF3	NM_001206998.2	MANE Select	c.300+20252C>T		intron	N/A	NP_001193927.1	Q9ULT6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNRF3	ENST00000544604.7	TSL:1 MANE Select	c.300+20252C>T		intron	N/A	ENSP00000443824.2	Q9ULT6-1
	ZNRF3	ENST00000920451.1		c.300+20252C>T		intron	N/A	ENSP00000590510.1
	ZNRF3	ENST00000920452.1		c.300+20252C>T		intron	N/A	ENSP00000590511.1

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

African (AFR) AF: 0.0422 AC: 1754 AN: 41530

American (AMR) AF: 0.140 AC: 2131 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 569 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2206 AN: 5166

South Asian (SAS) AF: 0.283 AC: 1364 AN: 4822

European-Finnish (FIN) AF: 0.148 AC: 1567 AN: 10582

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10426 AN: 68004

Other (OTH) AF: 0.164 AC: 347 AN: 2112

Alfa AF: 0.156 Hom.: 7613

Bravo AF: 0.132

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.83
PhyloP100		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs16986825; hg19: chr22-29300306;