Variant 19-21057541-T-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000261560.10(ZNF430):c.1233T>A(p.Asn411Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,606,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N411Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ZNF430
ENST00000261560.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.93

Variant links:

Genes affected

ZNF430 (HGNC:20808): (zinc finger protein 430) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in substantia nigra development. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF430 links:

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=0.032559484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF430	NM_025189.4 linkuse as main transcript	c.1233T>A	p.Asn411Lys	missense_variant	5/5	ENST00000261560.10	NP_079465.3	Q9H8G1A8K360
ZNF430	NM_001172671.2 linkuse as main transcript	c.1230T>A	p.Asn410Lys	missense_variant	5/5		NP_001166142.1	Q2NKJ9A8K360
ZNF430	XM_047439464.1 linkuse as main transcript	c.1140T>A	p.Asn380Lys	missense_variant	4/4		XP_047295420.1
ZNF430	XM_047439465.1 linkuse as main transcript	c.1137T>A	p.Asn379Lys	missense_variant	4/4		XP_047295421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF430	ENST00000261560.10 linkuse as main transcript	c.1233T>A	p.Asn411Lys	missense_variant	5/5	1	NM_025189.4	ENSP00000261560.4		Q9H8G1

Frequencies

GnomAD3 genomes

AF:

0.0000206

AC:

AN:

145750

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:

0.0000452

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247124

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134460

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000448

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1460498

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000206

AC:

AN:

145750

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

71178

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:

0.0000452

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

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

Dec 28, 2022

The c.1233T>A (p.N411K) alteration is located in exon 5 (coding exon 5) of the ZNF430 gene. This alteration results from a T to A substitution at nucleotide position 1233, causing the asparagine (N) at amino acid position 411 to be replaced by a lysine (K). 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

0.45

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.086

DANN

Benign

0.19

DEOGEN2

Benign

0.014

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0044

LIST_S2

Benign

0.023

M_CAP

Benign

0.00085

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.47

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.99

REVEL

Benign

0.014

Sift

Benign

0.69

Sift4G

Benign

0.85

Polyphen

0.0040

Vest4

0.075

MutPred

0.38

Gain of methylation at N411 (P = 0.0016);

MVP

0.030

MPC

0.16

ClinPred

0.019

GERP RS

-2.1

Varity_R

0.027

gMVP

0.015

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