22-29046827-A-C

Position:

• chr22-29046827-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001206998.2(ZNRF3):​c.856A>C​(p.Ser286Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3169638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNRF3	NM_001206998.2	c.856A>C	p.Ser286Arg	missense_variant	6/9	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4	c.556A>C	p.Ser186Arg	missense_variant	6/9		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNRF3	ENST00000544604.7	c.856A>C	p.Ser286Arg	missense_variant	6/9	1	NM_001206998.2	ENSP00000443824.2
ZNRF3	ENST00000406323.3	c.556A>C	p.Ser186Arg	missense_variant	5/8	1		ENSP00000384553.3
ZNRF3	ENST00000402174.5	c.556A>C	p.Ser186Arg	missense_variant	6/9	2		ENSP00000384456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2024

The c.856A>C (p.S286R) alteration is located in exon 6 (coding exon 6) of the ZNRF3 gene. This alteration results from a A to C substitution at nucleotide position 856, causing the serine (S) at amino acid position 286 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.49
MutPred		0.17		Loss of phosphorylation at S286 (P = 0.0384);.;.;
MVP		0.13
MPC		1.1
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs2037081396; hg19: chr22-29442815;