22-29048457-C-A
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2
The NM_001206998.2(ZNRF3):c.981C>A(p.His327Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,614,178 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: 𝑓 0.0035 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0045 ( 41 hom. )
Consequence
ZNRF3
NM_001206998.2 missense
NM_001206998.2 missense
Scores
5
8
5
Clinical Significance
Conservation
PhyloP100: 0.613
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 Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.022051662).
BP6
Variant 22-29048457-C-A is Benign according to our data. Variant chr22-29048457-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3341555.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00455 (6649/1461856) while in subpopulation MID AF= 0.0222 (128/5768). AF 95% confidence interval is 0.0191. There are 41 homozygotes in gnomad4_exome. There are 3431 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High AC in GnomAd4 at 533 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ZNRF3 | NM_001206998.2 | c.981C>A | p.His327Gln | missense_variant | 7/9 | ENST00000544604.7 | NP_001193927.1 | |
ZNRF3 | NM_032173.4 | c.681C>A | p.His227Gln | missense_variant | 7/9 | NP_115549.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ZNRF3 | ENST00000544604.7 | c.981C>A | p.His327Gln | missense_variant | 7/9 | 1 | NM_001206998.2 | ENSP00000443824.2 | ||
ZNRF3 | ENST00000406323.3 | c.681C>A | p.His227Gln | missense_variant | 6/8 | 1 | ENSP00000384553.3 | |||
ZNRF3 | ENST00000402174.5 | c.681C>A | p.His227Gln | missense_variant | 7/9 | 2 | ENSP00000384456.1 |
Frequencies
GnomAD3 genomes AF: 0.00350 AC: 533AN: 152204Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00454 AC: 1133AN: 249484Hom.: 4 AF XY: 0.00479 AC XY: 649AN XY: 135358
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GnomAD4 exome AF: 0.00455 AC: 6649AN: 1461856Hom.: 41 Cov.: 30 AF XY: 0.00472 AC XY: 3431AN XY: 727236
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GnomAD4 genome AF: 0.00350 AC: 533AN: 152322Hom.: 1 Cov.: 32 AF XY: 0.00367 AC XY: 273AN XY: 74480
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | ZNRF3: PP3, BS2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Loss of helix (P = 0.2022);.;.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at