Variant chr20-49247475-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_021035.3(ZNFX1):c.5549G>A(p.Arg1850His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

ZNFX1
NM_021035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08

Variant links:

Genes affected

ZNFX1 (HGNC:29271): (zinc finger NFX1-type containing 1) Enables RNA binding activity. Predicted to be involved in heterochromatin assembly by small RNA. Predicted to be part of nuclear RNA-directed RNA polymerase complex. [provided by Alliance of Genome Resources, Apr 2022]

ZNFX1 links:

Genome browser will be placed here

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;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZNFX1. . Gene score misZ 2.5616 (greater than the threshold 3.09). Trascript score misZ 4.0768 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency 91 and hyperinflammation.

BP4

Computational evidence support a benign effect (MetaRNN=0.09252682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNFX1	NM_021035.3 linkuse as main transcript	c.5549G>A	p.Arg1850His	missense_variant	14/14	ENST00000396105.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNFX1	ENST00000396105.6 linkuse as main transcript	c.5549G>A	p.Arg1850His	missense_variant	14/14	1	NM_021035.3	P1	Q9P2E3-1
ZNFX1	ENST00000371754.8 linkuse as main transcript	c.3312+4052G>A		intron_variant		1
ZNFX1	ENST00000371752.5 linkuse as main transcript	c.5549G>A	p.Arg1850His	missense_variant	14/14	5		P1	Q9P2E3-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251416

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.5549G>A (p.R1850H) alteration is located in exon 14 (coding exon 13) of the ZNFX1 gene. This alteration results from a G to A substitution at nucleotide position 5549, causing the arginine (R) at amino acid position 1850 to be replaced by a histidine (H). 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

0.12

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

T;T

Eigen

Benign

0.031

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.97

.;D

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.093

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.64

N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.90

P;P

Vest4

0.18

MVP

0.19

MPC

0.73

ClinPred

0.10

GERP RS

5.1

Varity_R

0.10

gMVP

0.40

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