Variant 19-8510886-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001146175.2(ZNF414):c.1064C>T(p.Pro355Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,124,106 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 6 hom. )

Consequence

ZNF414
NM_001146175.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0810

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041778684).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF414	NM_001146175.2 linkuse as main transcript	c.1064C>T	p.Pro355Leu	missense_variant	7/8	ENST00000393927.9	NP_001139647.1	Q96IQ9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9 linkuse as main transcript	c.1064C>T	p.Pro355Leu	missense_variant	7/8	1	NM_001146175.2	ENSP00000377504.3		Q96IQ9-2
ZNF414	ENST00000596772.5 linkuse as main transcript	c.272C>T	p.Pro91Leu	missense_variant	3/3	2		ENSP00000471378.1		M0R0Q5

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

255

AN:

145660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000407

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00523

Gnomad MID

AF:

0.00327

Gnomad NFE

AF:

0.00290

Gnomad OTH

AF:

0.000492

GnomAD3 exomes

AF:

0.00496

AC:

AN:

3632

Hom.:

AF XY:

0.00485

AC XY:

AN XY:

2062

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:

0.00729

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00120

AC:

1175

AN:

978334

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

577

AN XY:

460962

show subpopulations

Gnomad4 AFR exome

AF:

0.000154

Gnomad4 AMR exome

AF:

0.00108

Gnomad4 ASJ exome

AF:

0.0000969

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.00653

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.00174

AC:

254

AN:

145772

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

132

AN XY:

70920

show subpopulations

Gnomad4 AFR

AF:

0.000147

Gnomad4 AMR

AF:

0.000407

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.00523

Gnomad4 NFE

AF:

0.00290

Gnomad4 OTH

AF:

0.000487

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.000963

ExAC

AF:

0.000406

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 12, 2021

The c.1064C>T (p.P355L) alteration is located in exon 7 (coding exon 7) of the ZNF414 gene. This alteration results from a C to T substitution at nucleotide position 1064, causing the proline (P) at amino acid position 355 to be replaced by a leucine (L). 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

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.6

DANN

Benign

0.80

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.44

M_CAP

Benign

0.036

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.58

REVEL

Benign

0.019

Sift

Benign

0.034

Sift4G

Uncertain

0.0050

Vest4

0.079

MVP

0.072

MPC

0.23

ClinPred

0.013

GERP RS

-0.055

gMVP

0.20

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