22-29057205-G-C

Variant names:

• chr22-29057205-G-C
• rs12321
• NM_001206998.2:c.*3583G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

The NM_001206998.2(ZNRF3):​c.*3583G>C variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.39 in 151,930 control chromosomes in the GnomAD database, including 12,179 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 0.39 (12179 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: ZNRF3 NM_001206998.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35
• Publications: 14 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.492 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNRF3	NM_001206998.2	MANE Select	c.*3583G>C		3_prime_UTR	Exon 9 of 9	NP_001193927.1
	ZNRF3	NM_032173.4		c.*3583G>C		3_prime_UTR	Exon 9 of 9	NP_115549.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNRF3	ENST00000544604.7	TSL:1 MANE Select	c.*3583G>C		3_prime_UTR	Exon 9 of 9	ENSP00000443824.2

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59224 AN: 151812 Hom.: 12159 Cov.: 33

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.426

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.390 AC: 59265 AN: 151930 Hom.: 12179 Cov.: 33 AF XY: 0.394 AC XY: 29228 AN XY: 74248

African (AFR) AF: 0.265 AC: 10967 AN: 41432

American (AMR) AF: 0.443 AC: 6757 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1917 AN: 3470

East Asian (EAS) AF: 0.468 AC: 2416 AN: 5166

South Asian (SAS) AF: 0.508 AC: 2448 AN: 4816

European-Finnish (FIN) AF: 0.405 AC: 4268 AN: 10528

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29052 AN: 67940

Other (OTH) AF: 0.429 AC: 905 AN: 2110

Alfa AF: 0.245 Hom.: 602

Bravo AF: 0.385

Asia WGS AF: 0.468 AC: 1617 AN: 3454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.91
PhyloP100		7.4
Mutation Taster		=97/3	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12321; hg19: chr22-29453193;