22-28883913-G-T

Variant names:

• chr22-28883913-G-T
• NM_001206998.2:c.147G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001206998.2(ZNRF3):​c.147G>T​(p.Gly49Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNRF3 NM_001206998.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.139
• Publications: 0 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

ENSG00000302057 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 22-28883913-G-T is Benign according to our data. Variant chr22-28883913-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2672901.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.139 with no splicing effect.

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.147G>T	p.Gly49Gly	synonymous	Exon 1 of 9	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.147G>T	p.Gly49Gly	synonymous	Exon 1 of 9	ENSP00000443824.2	Q9ULT6-1
	ZNRF3	ENST00000920451.1		c.147G>T	p.Gly49Gly	synonymous	Exon 1 of 9	ENSP00000590510.1
	ZNRF3	ENST00000920452.1		c.147G>T	p.Gly49Gly	synonymous	Exon 1 of 8	ENSP00000590511.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1025044 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 499758

African (AFR) AF: 0.00 AC: 0 AN: 20058

American (AMR) AF: 0.00 AC: 0 AN: 16138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13380

East Asian (EAS) AF: 0.00 AC: 0 AN: 10800

South Asian (SAS) AF: 0.00 AC: 0 AN: 45106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 868298

Other (OTH) AF: 0.00 AC: 0 AN: 36280

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.95
PhyloP100		0.14
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

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

Other links and lift over

hg19: chr22-29279901;