Variant chr7-30285452-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000323037.5(ZNRF2):c.95A>G(p.Asn32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000045 in 1,155,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

ZNRF2
ENST00000323037.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.192

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:

LOC105375218 (HGNC:):

LOC105375218 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.032202244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNRF2	NM_147128.4 linkuse as main transcript	c.95A>G	p.Asn32Ser	missense_variant	1/5	ENST00000323037.5	NP_667339.1
LOC105375218	NR_136267.1 linkuse as main transcript	n.26+608T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNRF2	ENST00000323037.5 linkuse as main transcript	c.95A>G	p.Asn32Ser	missense_variant	1/5	1	NM_147128.4	ENSP00000323879	P1

Frequencies

GnomAD3 genomes

AF:

0.0000412

AC:

AN:

145620

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:

0.000411

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000611

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000455

AC:

AN:

1010184

Hom.:

Cov.:

AF XY:

0.0000447

AC XY:

AN XY:

492044

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:

0.0000688

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000460

Gnomad4 OTH exome

AF:

0.0000841

GnomAD4 genome

AF:

0.0000412

AC:

AN:

145620

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

70866

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000411

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000611

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000823

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

May 20, 2024

The c.95A>G (p.N32S) alteration is located in exon 1 (coding exon 1) of the ZNRF2 gene. This alteration results from a A to G substitution at nucleotide position 95, causing the asparagine (N) at amino acid position 32 to be replaced by a serine (S). 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

0.064

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.0025

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.45

M_CAP

Benign

0.031

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.0

REVEL

Benign

0.020

Sift

Benign

0.41

Sift4G

Benign

0.76

Polyphen

0.0010

Vest4

0.076

MutPred

0.21

Gain of glycosylation at N32 (P = 4e-04);

MVP

0.043

MPC

0.53

ClinPred

0.042

GERP RS

-0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.13

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