Genetic Variant ZNF431:p.Cys214Phe (chr19-21182944-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_133473.4(ZNF431):c.641G>T(p.Cys214Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,614,028 control chromosomes in the GnomAD database, including 25 homozygotes. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 24 hom. )

Consequence

ZNF431
NM_133473.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.267

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005800724).

BP6

Variant 19-21182944-G-T is Benign according to our data. Variant chr19-21182944-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1338686.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133473.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF431	NM_133473.4	MANE Select	c.641G>T	p.Cys214Phe	missense	Exon 5 of 5	NP_597730.2	Q8TF32
ZNF431	NM_001319124.2		c.644G>T	p.Cys215Phe	missense	Exon 5 of 5	NP_001306053.1
ZNF431	NM_001319126.2		c.368G>T	p.Cys123Phe	missense	Exon 6 of 6	NP_001306055.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF431	ENST00000311048.11	TSL:1 MANE Select	c.641G>T	p.Cys214Phe	missense	Exon 5 of 5	ENSP00000308578.6	Q8TF32
ZNF431	ENST00000949855.1		c.764G>T	p.Cys255Phe	missense	Exon 6 of 6	ENSP00000619914.1
ZNF431	ENST00000949854.1		c.692G>T	p.Cys231Phe	missense	Exon 6 of 6	ENSP00000619913.1

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

556

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00482

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00436

AC:

1091

AN:

250306

AF XY:

0.00424

show subpopulations

Gnomad AFR exome

AF:

0.000443

Gnomad AMR exome

AF:

0.00313

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.00461

Gnomad OTH exome

AF:

0.00675

GnomAD4 exome

AF:

0.00511

AC:

7470

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

3677

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33480

American (AMR)

AF:

0.00313

AC:

140

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00161

AC:

139

AN:

86246

European-Finnish (FIN)

AF:

0.0163

AC:

869

AN:

53410

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00544

AC:

6053

AN:

1111934

Other (OTH)

AF:

0.00389

AC:

235

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

444

887

1331

1774

2218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

232

464

696

928

1160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00366

AC:

557

AN:

152280

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41570

American (AMR)

AF:

0.00196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000831

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0155

AC:

164

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00482

AC:

328

AN:

68008

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00362

Hom.:

Bravo

AF:

0.00264

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00489

AC:

ExAC

AF:

0.00394

AC:

478

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00480

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.3

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.11

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.061

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.025

PhyloP100

-0.27

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-8.4

REVEL

Benign

0.059

Sift

Benign

0.26

Sift4G

Benign

0.70

Polyphen

0.058

Vest4

0.095

MVP

0.072

MPC

0.62

ClinPred

0.017

GERP RS

-1.6

Varity_R

0.17

gMVP

0.0083

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over