22-29048396-G-A

Position:

• chr22-29048396-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001206998.2(ZNRF3):​c.920G>A​(p.Arg307Gln) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P: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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 22-29048396-G-A is Pathogenic according to our data. Variant chr22-29048396-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3238963.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNRF3	NM_001206998.2	c.920G>A	p.Arg307Gln	missense_variant	7/9	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4	c.620G>A	p.Arg207Gln	missense_variant	7/9		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNRF3	ENST00000544604.7	c.920G>A	p.Arg307Gln	missense_variant	7/9	1	NM_001206998.2	ENSP00000443824.2
ZNRF3	ENST00000406323.3	c.620G>A	p.Arg207Gln	missense_variant	6/8	1		ENSP00000384553.3
ZNRF3	ENST00000402174.5	c.620G>A	p.Arg207Gln	missense_variant	7/9	2		ENSP00000384456.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZNRF3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Medical Genetics, University of Zurich

May 29, 2024

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.42	T;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.69		Loss of sheet (P = 0.0817);.;.;
MVP		0.71
MPC		1.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr22-29444384; COSMIC: COSV60435888;