22-29046849-G-A

Variant names:

• chr22-29046849-G-A
• NM_001206998.2:c.878G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001206998.2(ZNRF3):​c.878G>A​(p.Cys293Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a zinc_finger_region RING-type; atypical (size 41) in uniprot entity ZNRF3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001206998.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 22-29046849-G-A is Pathogenic according to our data. Variant chr22-29046849-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3238961.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNRF3	NM_001206998.2	c.878G>A	p.Cys293Tyr	missense_variant	Exon 6 of 9	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4	c.578G>A	p.Cys193Tyr	missense_variant	Exon 6 of 9		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNRF3	ENST00000544604.7	c.878G>A	p.Cys293Tyr	missense_variant	Exon 6 of 9	1	NM_001206998.2	ENSP00000443824.2
ZNRF3	ENST00000406323.3	c.578G>A	p.Cys193Tyr	missense_variant	Exon 5 of 8	1		ENSP00000384553.3
ZNRF3	ENST00000402174.5	c.578G>A	p.Cys193Tyr	missense_variant	Exon 6 of 9	2		ENSP00000384456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ZNRF3-related disorder Pathogenic:1

May 29, 2024

Institute of Medical Genetics, University of Zurich

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria applied: PS3 (Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product), PM1 (Located in a mutational hot spot and/or critical and well-established functional domain), PM6 (assumed de novo), PM2 (absent from controls), PP3 (in silico programs predict a deleterious effect) -

not provided Uncertain:1

Oct 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo variant with confirmed parentage in a patient with speech delay and macrocephaly in published literature (PMID: 39168120); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35982159, 33057194, 39168120, 31785789) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	5.0	H;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.8	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.89
MutPred		0.97		Gain of phosphorylation at C293 (P = 0.041);.;.;
MVP		0.81
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29442837;