rs5762919

Variant names:

• chr22-28967356-T-C
• rs5762919
• NM_001206998.2:c.301-19720T>C

Variant summary

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

The NM_001206998.2(ZNRF3):​c.301-19720T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 152,196 control chromosomes in the GnomAD database, including 1,171 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 0.10 (1171 hom., cov: 31)
• Consequence: ZNRF3 NM_001206998.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.59
• Publications: 3 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNRF3	NM_001206998.2	c.301-19720T>C		intron_variant	Intron 1 of 8	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4	c.1-19720T>C		intron_variant	Intron 1 of 8		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNRF3	ENST00000544604.7	c.301-19720T>C		intron_variant	Intron 1 of 8	1	NM_001206998.2	ENSP00000443824.2
ZNRF3	ENST00000402174.5	c.1-19720T>C		intron_variant	Intron 1 of 8	2		ENSP00000384456.1

Frequencies

GnomAD3 genomes AF: 0.0999 AC: 15185 AN: 152078 Hom.: 1159 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0754

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0698

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0834

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

GnomAD4 genome AF: 0.100 AC: 15236 AN: 152196 Hom.: 1171 Cov.: 31 AF XY: 0.102 AC XY: 7588 AN XY: 74416

African (AFR) AF: 0.212 AC: 8814 AN: 41492

American (AMR) AF: 0.0758 AC: 1161 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3470

East Asian (EAS) AF: 0.150 AC: 776 AN: 5168

South Asian (SAS) AF: 0.124 AC: 598 AN: 4818

European-Finnish (FIN) AF: 0.0698 AC: 741 AN: 10610

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2715 AN: 68016

Other (OTH) AF: 0.0825 AC: 174 AN: 2108

Alfa AF: 0.0583 Hom.: 270

Bravo AF: 0.104

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.42
DANN	Benign	0.33
PhyloP100		-2.6
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: rs5762919; hg19: chr22-29363344;