Variant 22-29049627-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001206998.2(ZNRF3):c.1446G>C(p.Gln482His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,610,994 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

ZNRF3
NM_001206998.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023358136).

BS2

High AC in GnomAd at 150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNRF3	NM_001206998.2 linkuse as main transcript	c.1446G>C	p.Gln482His	missense_variant	8/9	ENST00000544604.7
ZNRF3	NM_032173.4 linkuse as main transcript	c.1146G>C	p.Gln382His	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNRF3	ENST00000544604.7 linkuse as main transcript	c.1446G>C	p.Gln482His	missense_variant	8/9	1	NM_001206998.2	A2	Q9ULT6-1
ZNRF3	ENST00000406323.3 linkuse as main transcript	c.1146G>C	p.Gln382His	missense_variant	7/8	1		P2	Q9ULT6-2
ZNRF3	ENST00000402174.5 linkuse as main transcript	c.1146G>C	p.Gln382His	missense_variant	8/9	2		P2	Q9ULT6-2

Frequencies

GnomAD3 genomes

AF:

0.000985

AC:

150

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00115

AC:

278

AN:

241894

Hom.:

AF XY:

0.00108

AC XY:

142

AN XY:

131664

show subpopulations

Gnomad AFR exome

AF:

0.000395

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.00228

Gnomad NFE exome

AF:

0.00196

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.00153

AC:

2234

AN:

1458648

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

1036

AN XY:

725730

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00249

Gnomad4 NFE exome

AF:

0.00182

Gnomad4 OTH exome

AF:

0.000895

GnomAD4 genome

AF:

0.000985

AC:

150

AN:

152346

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00166

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.000876

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000475

AC:

ESP6500EA

AF:

0.00191

AC:

ExAC

AF:

0.00117

AC:

141

EpiCase

AF:

0.00158

EpiControl

AF:

0.00148

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

Nov 30, 2021

The c.1446G>C (p.Q482H) alteration is located in exon 8 (coding exon 8) of the ZNRF3 gene. This alteration results from a G to C substitution at nucleotide position 1446, causing the glutamine (Q) at amino acid position 482 to be replaced by a histidine (H). 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

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.080

T;.;.

Eigen

Benign

0.10

Eigen_PC

Benign

0.067

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.77

T;.;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Uncertain

0.066

MutationAssessor

Uncertain

2.2

M;.;.

MutationTaster

Benign

0.96

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.020

D;T;T

Polyphen

1.0

D;.;.

Vest4

0.42

MutPred

0.21

Loss of solvent accessibility (P = 0.0238);.;.;

MVP

0.51

MPC

1.1

ClinPred

0.041

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.61

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