Variant 20-49247282-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_021035.3(ZNFX1):c.5742C>G(p.Ile1914Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000809 in 1,607,202 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ZNFX1
NM_021035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.412

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 Likely_benign. 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=0.06511852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNFX1	NM_021035.3 linkuse as main transcript	c.5742C>G	p.Ile1914Met	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.5742C>G	p.Ile1914Met	missense_variant	14/14	1	NM_021035.3	P1	Q9P2E3-1
ZNFX1	ENST00000371754.8 linkuse as main transcript	c.3312+4245C>G		intron_variant		1
ZNFX1	ENST00000371752.5 linkuse as main transcript	c.5742C>G	p.Ile1914Met	missense_variant	14/14	5		P1	Q9P2E3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000825

AC:

AN:

1455006

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

722754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Asia WGS

AF:

0.00115

AC:

AN:

3478

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

Dec 11, 2023

The c.5742C>G (p.I1914M) alteration is located in exon 14 (coding exon 13) of the ZNFX1 gene. This alteration results from a C to G substitution at nucleotide position 5742, causing the isoleucine (I) at amino acid position 1914 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

Benign

0.10

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.010

T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.55

.;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.49

N;N

REVEL

Benign

0.12

Sift

Benign

0.078

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.15

B;B

Vest4

0.086

MutPred

0.37

Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);

MVP

0.33

MPC

0.50

ClinPred

0.060

GERP RS

1.8

Varity_R

0.049

gMVP

0.18

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