Variant 7-30285401-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_147128.4(ZNRF2):c.44C>T(p.Thr15Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,260,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

ZNRF2
NM_147128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44

Variant links:

Genes affected

ZNRF2 (HGNC:22316): (zinc and ring finger 2) Enables ubiquitin protein ligase activity. Predicted to be involved in protein ubiquitination. Located in cytoplasmic vesicle membrane; nuclear lumen; and plasma membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ZNRF2 links:

ZNRF2 (HGNC:):

ZNRF2 links:

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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=0.22817016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNRF2	NM_147128.4 linkuse as main transcript	c.44C>T	p.Thr15Met	missense_variant	1/5	ENST00000323037.5	NP_667339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNRF2	ENST00000323037.5 linkuse as main transcript	c.44C>T	p.Thr15Met	missense_variant	1/5	1	NM_147128.4	ENSP00000323879.4		Q8NHG8

Frequencies

GnomAD3 genomes

AF:

0.0000542

AC:

AN:

147736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000121

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1112878

Hom.:

Cov.:

AF XY:

0.0000419

AC XY:

AN XY:

548474

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000424

Gnomad4 OTH exome

AF:

0.0000734

GnomAD4 genome

AF:

0.0000542

AC:

AN:

147736

Hom.:

Cov.:

AF XY:

0.0000695

AC XY:

AN XY:

71928

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000121

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

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

Sep 23, 2023

The c.44C>T (p.T15M) alteration is located in exon 1 (coding exon 1) of the ZNRF2 gene. This alteration results from a C to T substitution at nucleotide position 44, causing the threonine (T) at amino acid position 15 to be replaced by a methionine (M). 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

Uncertain

0.54

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

Eigen

Benign

0.024

Eigen_PC

Benign

-0.013

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.38

Sift

Benign

0.037

Sift4G

Uncertain

0.053

Polyphen

1.0

Vest4

0.25

MutPred

0.26

Loss of phosphorylation at T15 (P = 0.0292);

MVP

0.068

MPC

1.7

ClinPred

0.86

GERP RS

2.7

Varity_R

0.083

gMVP

0.54

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