Genetic Variant ZNRF4:p.Pro6Leu (chr19-5455508-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181710.4(ZNRF4):c.17C>T(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,609,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ZNRF4
NM_181710.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.98

Variant links:

Genes affected

ZNRF4 (HGNC:17726): (zinc and ring finger 4) Predicted to enable ubiquitin protein ligase activity. Involved in ubiquitin-dependent protein catabolic process. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZNRF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074281126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNRF4	NM_181710.4 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 1	ENST00000222033.6	NP_859061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNRF4	ENST00000222033.6 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 1	6	NM_181710.4	ENSP00000222033.4		Q8WWF5

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000490

AC:

AN:

245110

Hom.:

AF XY:

0.0000751

AC XY:

AN XY:

133150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000876

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000538

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000131

AC:

191

AN:

1457330

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

724668

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000156

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.00000825

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17C>T (p.P6L) alteration is located in exon 1 (coding exon 1) of the ZNRF4 gene. This alteration results from a C to T substitution at nucleotide position 17, causing the proline (P) at amino acid position 6 to be replaced by a leucine (L). 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

-0.49

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.8

DANN

Benign

0.97

DEOGEN2

Benign

0.0017

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.35

M_CAP

Benign

0.014

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.49

REVEL

Benign

0.026

Sift

Uncertain

0.016

Sift4G

Pathogenic

0.0

Polyphen

0.20

Vest4

0.042

MutPred

0.32

Gain of MoRF binding (P = 0.0243);

MVP

0.040

MPC

0.25

ClinPred

0.040

GERP RS

-5.6

Varity_R

0.038

gMVP

0.17

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