Variant 19-22757320-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001080409.3(ZNF99):c.2589G>A(p.Met863Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,451,674 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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: 0.00014 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

ZNF99
NM_001080409.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.33

Variant links:

Genes affected

ZNF99 (HGNC:13175): (zinc finger protein 99) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF99 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057643354).

BP6

Variant 19-22757320-C-T is Benign according to our data. Variant chr19-22757320-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2349447.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF99	NM_001080409.3 linkuse as main transcript	c.2589G>A	p.Met863Ile	missense_variant	4/4	ENST00000596209.4	NP_001073878.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF99	ENST00000596209.4 linkuse as main transcript	c.2589G>A	p.Met863Ile	missense_variant	4/4	5	NM_001080409.3	ENSP00000472969	P1

Frequencies

GnomAD3 genomes

AF:

0.00366

AC:

504

AN:

137822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00172

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000449

Gnomad SAS

AF:

0.000471

Gnomad FIN

AF:

0.000216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00723

GnomAD3 exomes

AF:

0.000276

AC:

AN:

242844

Hom.:

AF XY:

0.000220

AC XY:

AN XY:

131956

show subpopulations

Gnomad AFR exome

AF:

0.00373

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000685

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000359

Gnomad OTH exome

AF:

0.000343

GnomAD4 exome

AF:

0.000136

AC:

197

AN:

1451674

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

722094

show subpopulations

Gnomad4 AFR exome

AF:

0.00397

Gnomad4 AMR exome

AF:

0.000298

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000353

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000226

Gnomad4 OTH exome

AF:

0.000435

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00365

AC:

504

AN:

137938

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

253

AN XY:

67396

show subpopulations

Gnomad4 AFR

AF:

0.0122

Gnomad4 AMR

AF:

0.00171

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000450

Gnomad4 SAS

AF:

0.000471

Gnomad4 FIN

AF:

0.000216

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00714

Alfa

AF:

0.000788

Hom.:

ExAC

AF:

0.000273

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.16

DANN

Benign

0.83

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00046

LIST_S2

Benign

0.038

M_CAP

Benign

0.00027

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

PROVEAN

Benign

0.60

REVEL

Benign

0.029

Sift

Benign

0.82

Sift4G

Benign

0.26

Vest4

0.19

MVP

0.014

ClinPred

0.0028

GERP RS

-0.51

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