NM_001080409.3:c.2589G>A

Variant names:

• chr19-22757320-C-T
• rs767848190
• NM_001080409.3:c.2589G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 14/18 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.33
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 2349447.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080409.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF99	NM_001080409.3	MANE Select	c.2589G>A	p.Met863Ile	missense	Exon 4 of 4	NP_001073878.2	A8MXY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF99	ENST00000596209.4	TSL:5 MANE Select	c.2589G>A	p.Met863Ile	missense	Exon 4 of 4	ENSP00000472969.1	A8MXY4

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 504 AN: 137822 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.000276 AC: 67 AN: 242844 AF XY: 0.000220

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 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.: 7 Cov.: 47 AF XY: 0.000125 AC XY: 90 AN XY: 722094

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00397 AC: 129 AN: 32474

American (AMR) AF: 0.000298 AC: 13 AN: 43602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.0000353 AC: 3 AN: 84930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52618

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5720

European-Non Finnish (NFE) AF: 0.0000226 AC: 25 AN: 1107368

Other (OTH) AF: 0.000435 AC: 26 AN: 59838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00365 AC: 504 AN: 137938 Hom.: 1 Cov.: 33 AF XY: 0.00375 AC XY: 253 AN XY: 67396

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0122 AC: 447 AN: 36724

American (AMR) AF: 0.00171 AC: 24 AN: 13998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3252

East Asian (EAS) AF: 0.000450 AC: 2 AN: 4448

South Asian (SAS) AF: 0.000471 AC: 2 AN: 4242

European-Finnish (FIN) AF: 0.000216 AC: 2 AN: 9240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 188

European-Non Finnish (NFE) AF: 0.000221 AC: 14 AN: 63228

Other (OTH) AF: 0.00714 AC: 13 AN: 1820

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000788 Hom.: 0

ExAC AF: 0.000273 AC: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
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	N
LIST_S2	Benign	0.038	T
M_CAP	Benign	0.00027	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.96	T
PhyloP100		-2.3
PROVEAN	Benign	0.60	N
REVEL	Benign	0.029
Sift	Benign	0.82	T
Sift4G	Benign	0.26	T
Vest4		0.19
MVP		0.014
ClinPred		0.0028	T
GERP RS		-0.51
Varity_R		0.065
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs767848190; hg19: chr19-22940122; COSMIC: COSV68057666;