Genetic Variant NM_001080409.3:c.2582A>G (chr19-22757327-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001080409.3(ZNF99):c.2582A>G(p.Glu861Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000072 ( 5 hom. )

Failed GnomAD Quality Control

Consequence

ZNF99
NM_001080409.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.12

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011672348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF99	NM_001080409.3 link	c.2582A>G	p.Glu861Gly	missense_variant	Exon 4 of 4	ENST00000596209.4	NP_001073878.2	A8MXY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF99	ENST00000596209.4 link	c.2582A>G	p.Glu861Gly	missense_variant	Exon 4 of 4	5	NM_001080409.3	ENSP00000472969.1		A8MXY4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

365

AN:

149646

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00835

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00113

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:

0.0000592

Gnomad OTH

AF:

0.00490

GnomAD3 exomes

AF:

0.000130

AC:

AN:

246728

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

134154

show subpopulations

Gnomad AFR exome

AF:

0.00182

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000719

AC:

105

AN:

1459832

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

726332

show subpopulations

Gnomad4 AFR exome

AF:

0.00228

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00244

AC:

365

AN:

149774

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

180

AN XY:

73260

show subpopulations

Gnomad4 AFR

AF:

0.00832

Gnomad4 AMR

AF:

0.00112

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000592

Gnomad4 OTH

AF:

0.00484

Alfa

AF:

0.000800

Hom.:

ExAC

AF:

0.000215

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2582A>G (p.E861G) alteration is located in exon 4 (coding exon 4) of the ZNF99 gene. This alteration results from a A to G substitution at nucleotide position 2582, causing the glutamic acid (E) at amino acid position 861 to be replaced by a glycine (G). 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

0.080

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.45

DANN

Benign

0.40

DEOGEN2

Benign

0.027

FATHMM_MKL

Benign

0.0079

LIST_S2

Benign

0.16

M_CAP

Benign

0.00043

MetaRNN

Benign

0.012

PrimateAI

Benign

0.27

Sift4G

Benign

0.30

Vest4

0.041

MVP

0.030

MPC

0.016

GERP RS

-1.9

Varity_R

0.027

gMVP

0.030

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