22-28987086-T-C

Position:

• chr22-28987086-T-C

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.311T>C​(p.Leu104Pro) 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: 32)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.37

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, 0.859
• PP5: Variant 22-28987086-T-C is Pathogenic according to our data. Variant chr22-28987086-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3238957.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.311T>C	p.Leu104Pro	missense_variant	2/9	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4	c.11T>C	p.Leu4Pro	missense_variant	2/9		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNRF3	ENST00000544604.7	c.311T>C	p.Leu104Pro	missense_variant	2/9	1	NM_001206998.2	ENSP00000443824.2
ZNRF3	ENST00000406323.3	c.11T>C	p.Leu4Pro	missense_variant	1/8	1		ENSP00000384553.3
ZNRF3	ENST00000402174.5	c.11T>C	p.Leu4Pro	missense_variant	2/9	2		ENSP00000384456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.59		Gain of catalytic residue at P103 (P = 0.0139);.;.;
MVP		0.64
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.82

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: chr22-29383074;