chr19-5455597-C-T

Variant summary

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

The NM_181710.4(ZNRF4):​c.106C>T​(p.Arg36Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,122 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

ZNRF4
NM_181710.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0560
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]

Genome browser will be placed here

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=0.013062358).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNRF4NM_181710.4 linkc.106C>T p.Arg36Cys missense_variant Exon 1 of 1 ENST00000222033.6 NP_859061.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNRF4ENST00000222033.6 linkc.106C>T p.Arg36Cys missense_variant Exon 1 of 1 6 NM_181710.4 ENSP00000222033.4 Q8WWF5

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152206
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00116
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000932
AC:
23
AN:
246848
Hom.:
0
AF XY:
0.0000968
AC XY:
13
AN XY:
134362
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00106
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000206
AC:
30
AN:
1459798
Hom.:
1
Cov.:
31
AF XY:
0.0000262
AC XY:
19
AN XY:
726342
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000277
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152324
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000992
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.106C>T (p.R36C) 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 106, causing the arginine (R) at amino acid position 36 to be replaced by a cysteine (C). 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
-0.52
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
15
DANN
Benign
0.97
DEOGEN2
Benign
0.0026
T
Eigen
Benign
-0.97
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.045
N
LIST_S2
Benign
0.51
T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.013
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.34
N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.44
N
REVEL
Benign
0.042
Sift
Uncertain
0.021
D
Sift4G
Uncertain
0.051
T
Polyphen
0.30
B
Vest4
0.19
MutPred
0.18
Loss of MoRF binding (P = 0.0083);
MVP
0.040
MPC
0.34
ClinPred
0.076
T
GERP RS
1.1
Varity_R
0.10
gMVP
0.15

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.

Other links and lift over

dbSNP: rs533579864; hg19: chr19-5455608; API