22-29053489-A-G

Variant names:

• chr22-29053489-A-G
• rs2294239
• NM_001206998.2:c.2768-90A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206998.2(ZNRF3):​c.2768-90A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,288,702 control chromosomes in the GnomAD database, including 116,093 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 0.37 (11125 hom., cov: 31)
  • Exomes 𝑓: 0.43 (104968 hom.)
• Consequence: ZNRF3 NM_001206998.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.29
• Publications: 35 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNRF3	NM_001206998.2	c.2768-90A>G		intron_variant	Intron 8 of 8	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4	c.2468-90A>G		intron_variant	Intron 8 of 8		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNRF3	ENST00000544604.7	c.2768-90A>G		intron_variant	Intron 8 of 8	1	NM_001206998.2	ENSP00000443824.2
ZNRF3	ENST00000406323.3	c.2468-90A>G		intron_variant	Intron 7 of 7	1		ENSP00000384553.3
ZNRF3	ENST00000402174.5	c.2468-90A>G		intron_variant	Intron 8 of 8	2		ENSP00000384456.1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55545 AN: 151806 Hom.: 11122 Cov.: 31

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.426 AC: 483741 AN: 1136778 Hom.: 104968 AF XY: 0.427 AC XY: 246444 AN XY: 576650

African (AFR) AF: 0.198 AC: 5232 AN: 26422

American (AMR) AF: 0.396 AC: 14390 AN: 36332

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 11636 AN: 21144

East Asian (EAS) AF: 0.488 AC: 18316 AN: 37548

South Asian (SAS) AF: 0.463 AC: 33522 AN: 72352

European-Finnish (FIN) AF: 0.396 AC: 20313 AN: 51238

Middle Eastern (MID) AF: 0.509 AC: 2288 AN: 4496

European-Non Finnish (NFE) AF: 0.426 AC: 356970 AN: 838344

Other (OTH) AF: 0.431 AC: 21074 AN: 48902

GnomAD4 genome AF: 0.366 AC: 55551 AN: 151924 Hom.: 11125 Cov.: 31 AF XY: 0.369 AC XY: 27398 AN XY: 74238

African (AFR) AF: 0.203 AC: 8435 AN: 41452

American (AMR) AF: 0.426 AC: 6511 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1890 AN: 3466

East Asian (EAS) AF: 0.461 AC: 2378 AN: 5158

South Asian (SAS) AF: 0.467 AC: 2240 AN: 4794

European-Finnish (FIN) AF: 0.401 AC: 4238 AN: 10560

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28509 AN: 67916

Other (OTH) AF: 0.405 AC: 854 AN: 2108

Alfa AF: 0.410 Hom.: 56380

Bravo AF: 0.359

Asia WGS AF: 0.435 AC: 1515 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.025
DANN	Benign	0.50
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2294239; hg19: chr22-29449477; COSMIC: COSV60438880;