Genetic Variant ZNF414:p.Pro235Gln (chr19-8511787-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001146175.2(ZNF414):c.704C>A(p.Pro235Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,413,658 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P235L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

ZNF414
NM_001146175.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.53

Publications

0 publications found

Variant links:

Genes affected

ZNF414 (HGNC:20630): (zinc finger protein 414) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ZNF414 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039008558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2 link	c.704C>A	p.Pro235Gln	missense_variant	Exon 5 of 8	ENST00000393927.9	NP_001139647.1	Q96IQ9-2
ZNF414	NM_032370.3 link	c.704C>A	p.Pro235Gln	missense_variant	Exon 5 of 6		NP_115746.2	Q96IQ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9 link	c.704C>A	p.Pro235Gln	missense_variant	Exon 5 of 8	1	NM_001146175.2	ENSP00000377504.3		Q96IQ9-2

Frequencies

GnomAD3 genomes

AF:

0.000782

AC:

119

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000214

AC:

AN:

51522

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.00321

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

147

AN:

1261382

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

612960

show subpopulations

African (AFR)

AF:

0.00365

AC:

AN:

25188

American (AMR)

AF:

0.000191

AC:

AN:

15720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17448

East Asian (EAS)

AF:

0.00

AC:

AN:

30972

South Asian (SAS)

AF:

0.0000170

AC:

AN:

58920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31976

Middle Eastern (MID)

AF:

0.000438

AC:

AN:

4564

European-Non Finnish (NFE)

AF:

0.0000283

AC:

AN:

1024534

Other (OTH)

AF:

0.000384

AC:

AN:

52060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000788

AC:

120

AN:

152276

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00279

AC:

116

AN:

41572

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67994

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000895

ESP6500AA

AF:

0.00128

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000265

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.010

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0017

.;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PhyloP100

-3.5

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.042

Sift

Benign

0.73

T;T

Sift4G

Benign

0.072

T;T

Polyphen

0.0010

.;B

Vest4

0.13

MVP

0.095

MPC

0.22

ClinPred

0.025

GERP RS

-8.9

PromoterAI

-0.041

Neutral

(source)

Varity_R

0.026

gMVP

0.27

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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19-8511787-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over