Variant 22-29049494-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001206998.2(ZNRF3):c.1313G>A(p.Arg438Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,452,552 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: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ZNRF3
NM_001206998.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.26

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33295652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNRF3	NM_001206998.2 linkuse as main transcript	c.1313G>A	p.Arg438Gln	missense_variant	8/9	ENST00000544604.7
ZNRF3	NM_032173.4 linkuse as main transcript	c.1013G>A	p.Arg338Gln	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNRF3	ENST00000544604.7 linkuse as main transcript	c.1313G>A	p.Arg438Gln	missense_variant	8/9	1	NM_001206998.2	A2	Q9ULT6-1
ZNRF3	ENST00000406323.3 linkuse as main transcript	c.1013G>A	p.Arg338Gln	missense_variant	7/8	1		P2	Q9ULT6-2
ZNRF3	ENST00000402174.5 linkuse as main transcript	c.1013G>A	p.Arg338Gln	missense_variant	8/9	2		P2	Q9ULT6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000416

AC:

AN:

240594

Hom.:

AF XY:

0.00000760

AC XY:

AN XY:

131502

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1452552

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 21, 2022

The c.1313G>A (p.R438Q) alteration is located in exon 8 (coding exon 8) of the ZNRF3 gene. This alteration results from a G to A substitution at nucleotide position 1313, causing the arginine (R) at amino acid position 438 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

0.079

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.078

T;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Uncertain

0.083

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

0.72

N;N;N;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.034

D;D;D

Sift4G

Benign

0.10

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.38

MutPred

0.34

Loss of methylation at R438 (P = 0.0479);.;.;

MVP

0.56

MPC

0.65

ClinPred

0.86

GERP RS

4.5

Varity_R

0.082

gMVP

0.55

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