Variant 19-21183385-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_133473.4(ZNF431):c.1082A>C(p.Lys361Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,612,754 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 0.00077 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

ZNF431
NM_133473.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -8.14

Variant links:

Genes affected

ZNF431 (HGNC:20809): (zinc finger protein 431) This gene encodes a member of the Krueppel C2H2-type zinc-finger family of proteins. The encoded protein may negatively regulate transcription of target genes, including the hedgehog signaling pathway receptor patched 1, by interacting with histone deacetylases. Mutations in this gene may be associated with non-syndromic facial clefting in human patients. [provided by RefSeq, Jul 2016]

ZNF431 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=0.019735128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF431	NM_133473.4 linkuse as main transcript	c.1082A>C	p.Lys361Thr	missense_variant	5/5	ENST00000311048.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ZNF431	ENST00000311048.11 linkuse as main transcript	c.1082A>C	p.Lys361Thr	missense_variant	5/5	1	NM_133473.4	P1
ZNF431	ENST00000600692.5 linkuse as main transcript	c.*669A>C		3_prime_UTR_variant	6/6	5
ZNF431	ENST00000594425.5 linkuse as main transcript	c.97-6480A>C		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000773

AC:

117

AN:

151412

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00152

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000627

AC:

156

AN:

248870

Hom.:

AF XY:

0.000564

AC XY:

AN XY:

134760

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.00139

AC:

2034

AN:

1461342

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

923

AN XY:

726962

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00175

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.000773

AC:

117

AN:

151412

Hom.:

Cov.:

AF XY:

0.000757

AC XY:

AN XY:

73948

show subpopulations

Gnomad4 AFR

AF:

0.000267

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00152

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000782

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000601

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

Aug 02, 2021

The c.1082A>C (p.K361T) alteration is located in exon 5 (coding exon 5) of the ZNF431 gene. This alteration results from a A to C substitution at nucleotide position 1082, causing the lysine (K) at amino acid position 361 to be replaced by a threonine (T). 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

0.22

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

Cadd

Benign

0.41

Dann

Benign

0.47

DEOGEN2

Benign

0.0027

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.051

M_CAP

Benign

0.0033

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.055

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.65

REVEL

Benign

0.018

Sift

Benign

0.42

Sift4G

Benign

0.53

Polyphen

0.0080

Vest4

0.12

MVP

0.092

MPC

0.12

ClinPred

0.017

GERP RS

1.0

Varity_R

0.023

gMVP

0.040

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