19-22757846-T-C

Variant names:

• chr19-22757846-T-C
• NM_001080409.3:c.2063A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080409.3(ZNF99):​c.2063A>G​(p.His688Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF99 NM_001080409.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.133
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05566901).

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.2063A>G	p.His688Arg	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.2063A>G	p.His688Arg	missense	Exon 4 of 4	ENSP00000472969.1	A8MXY4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460046 Hom.: 0 Cov.: 48 AF XY: 0.00000138 AC XY: 1 AN XY: 726324

African (AFR) AF: 0.0000300 AC: 1 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110744

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.31
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.35
DANN	Benign	0.57
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.013	T
M_CAP	Benign	0.00071	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.050	N
PhyloP100		-0.13
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.0080
Sift	Benign	0.67	T
Sift4G	Benign	0.61	T
Vest4		0.066
MVP		0.014
MPC		0.025
ClinPred		0.067	T
GERP RS		-2.2
Varity_R		0.028
gMVP		0.0047
Mutation Taster		=93/7	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

hg19: chr19-22940648;