Variant 22-29046795-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001206998.2(ZNRF3):c.824G>A(p.Arg275Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,611,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ZNRF3
NM_001206998.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.44

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]

ZNRF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16078681).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNRF3	NM_001206998.2 linkuse as main transcript	c.824G>A	p.Arg275Gln	missense_variant	6/9	ENST00000544604.7
ZNRF3	NM_032173.4 linkuse as main transcript	c.524G>A	p.Arg175Gln	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNRF3	ENST00000544604.7 linkuse as main transcript	c.824G>A	p.Arg275Gln	missense_variant	6/9	1	NM_001206998.2	A2	Q9ULT6-1
ZNRF3	ENST00000406323.3 linkuse as main transcript	c.524G>A	p.Arg175Gln	missense_variant	5/8	1		P2	Q9ULT6-2
ZNRF3	ENST00000402174.5 linkuse as main transcript	c.524G>A	p.Arg175Gln	missense_variant	6/9	2		P2	Q9ULT6-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

247918

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1459722

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726016

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.824G>A (p.R275Q) alteration is located in exon 6 (coding exon 6) of the ZNRF3 gene. This alteration results from a G to A substitution at nucleotide position 824, causing the arginine (R) at amino acid position 275 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.45

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.074

T;.;.

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.46

N;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.058

T;D;D

Sift4G

Benign

0.34

T;T;T

Polyphen

0.29

B;.;.

Vest4

0.26

MutPred

0.25

Loss of MoRF binding (P = 0.032);.;.;

MVP

0.11

MPC

1.2

ClinPred

0.41

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.22

gMVP

0.71

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over