22-29046849-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

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 Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ZNRF3
NM_001206998.2 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.60
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

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 [Pathogenic]. Clinvar id is 3238961.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNRF3NM_001206998.2 linkuse as main transcriptc.878G>A p.Cys293Tyr missense_variant 6/9 ENST00000544604.7 NP_001193927.1
ZNRF3NM_032173.4 linkuse as main transcriptc.578G>A p.Cys193Tyr missense_variant 6/9 NP_115549.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNRF3ENST00000544604.7 linkuse as main transcriptc.878G>A p.Cys293Tyr missense_variant 6/91 NM_001206998.2 ENSP00000443824.2 Q9ULT6-1
ZNRF3ENST00000406323.3 linkuse as main transcriptc.578G>A p.Cys193Tyr missense_variant 5/81 ENSP00000384553.3 Q9ULT6-2
ZNRF3ENST00000402174.5 linkuse as main transcriptc.578G>A p.Cys193Tyr missense_variant 6/92 ENSP00000384456.1 Q9ULT6-2

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
LINK: link

Submissions by phenotype

ZNRF3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterresearchInstitute of Medical Genetics, University of ZurichMay 29, 2024ACMG 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
0.46
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; API