22-29048457-C-A

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

Scores

5
8
5

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.613
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]

Genome browser will be placed here

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
ZNRF3NM_001206998.2 linkuse as main transcriptc.981C>A p.His327Gln missense_variant 7/9 ENST00000544604.7 NP_001193927.1
ZNRF3NM_032173.4 linkuse as main transcriptc.681C>A p.His227Gln missense_variant 7/9 NP_115549.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNRF3ENST00000544604.7 linkuse as main transcriptc.981C>A p.His327Gln missense_variant 7/91 NM_001206998.2 ENSP00000443824.2 Q9ULT6-1
ZNRF3ENST00000406323.3 linkuse as main transcriptc.681C>A p.His227Gln missense_variant 6/81 ENSP00000384553.3 Q9ULT6-2
ZNRF3ENST00000402174.5 linkuse as main transcriptc.681C>A p.His227Gln missense_variant 7/92 ENSP00000384456.1 Q9ULT6-2

Frequencies

GnomAD3 genomes
AF:
0.00350
AC:
533
AN:
152204
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000965
Gnomad AMI
AF:
0.00548
Gnomad AMR
AF:
0.00229
Gnomad ASJ
AF:
0.00260
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00600
Gnomad FIN
AF:
0.0103
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00435
Gnomad OTH
AF:
0.00383
GnomAD3 exomes
AF:
0.00454
AC:
1133
AN:
249484
Hom.:
4
AF XY:
0.00479
AC XY:
649
AN XY:
135358
show subpopulations
Gnomad AFR exome
AF:
0.000968
Gnomad AMR exome
AF:
0.00214
Gnomad ASJ exome
AF:
0.00159
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00614
Gnomad FIN exome
AF:
0.0127
Gnomad NFE exome
AF:
0.00471
Gnomad OTH exome
AF:
0.00561
GnomAD4 exome
AF:
0.00455
AC:
6649
AN:
1461856
Hom.:
41
Cov.:
30
AF XY:
0.00472
AC XY:
3431
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00158
Gnomad4 AMR exome
AF:
0.00228
Gnomad4 ASJ exome
AF:
0.00237
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00737
Gnomad4 FIN exome
AF:
0.0123
Gnomad4 NFE exome
AF:
0.00422
Gnomad4 OTH exome
AF:
0.00520
GnomAD4 genome
AF:
0.00350
AC:
533
AN:
152322
Hom.:
1
Cov.:
32
AF XY:
0.00367
AC XY:
273
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000962
Gnomad4 AMR
AF:
0.00229
Gnomad4 ASJ
AF:
0.00260
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00600
Gnomad4 FIN
AF:
0.0103
Gnomad4 NFE
AF:
0.00435
Gnomad4 OTH
AF:
0.00379
Alfa
AF:
0.00353
Hom.:
0
Bravo
AF:
0.00293
TwinsUK
AF:
0.00270
AC:
10
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.00139
AC:
6
ESP6500EA
AF:
0.00623
AC:
53
ExAC
AF:
0.00486
AC:
589
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.00523
EpiControl
AF:
0.00486

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 submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024ZNRF3: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Benign
-0.010
T
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
T;.;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.90
D;.;D
MetaRNN
Benign
0.022
T;T;T
MetaSVM
Uncertain
0.71
D
MutationAssessor
Benign
1.3
L;.;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-6.2
D;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.029
D;D;D
Sift4G
Uncertain
0.028
D;D;D
Polyphen
0.99
D;.;.
Vest4
0.88
MutPred
0.53
Loss of helix (P = 0.2022);.;.;
MVP
0.74
MPC
1.2
ClinPred
0.038
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.62
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs55775472; hg19: chr22-29444445; COSMIC: COSV60439108; API