19-57778933-C-T

Variant names:

• chr19-57778933-C-T
• rs200171139
• NM_017652.4:c.346C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017652.4(ZNF586):​c.346C>T​(p.Arg116Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,968 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: ZNF586 NM_017652.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.392
• Publications: 5 publications found

Genes affected

ZNF586 (HGNC:25949): (zinc finger protein 586) Predicted to enable DNA-binding transcription factor 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09548077).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017652.4. 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
	ZNF586	NM_017652.4	MANE Select	c.346C>T	p.Arg116Cys	missense	Exon 3 of 3	NP_060122.2	Q9NXT0-1
	ZNF586	NM_001204814.2		c.217C>T	p.Arg73Cys	missense	Exon 4 of 4	NP_001191743.1	Q9NXT0-3
	ZNF586	NM_001077426.3		c.219C>T	p.Phe73Phe	synonymous	Exon 2 of 2	NP_001070894.1	Q9NXT0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF586	ENST00000396154.7	TSL:1 MANE Select	c.346C>T	p.Arg116Cys	missense	Exon 3 of 3	ENSP00000379458.1	Q9NXT0-1
	ZNF586	ENST00000396150.4	TSL:1	c.219C>T	p.Phe73Phe	synonymous	Exon 2 of 2	ENSP00000379454.3	Q9NXT0-2
	ZNF586	ENST00000391702.3	TSL:2	c.217C>T	p.Arg73Cys	missense	Exon 4 of 4	ENSP00000375583.3	Q9NXT0-3

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000168 AC: 42 AN: 250132 AF XY: 0.000192

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.000208 AC XY: 151 AN XY: 727234

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000219 AC: 243 AN: 1112004

Other (OTH) AF: 0.000132 AC: 8 AN: 60394

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74296

African (AFR) AF: 0.000145 AC: 6 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000306 Hom.: 1

Bravo AF: 0.000276

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000218

EpiControl AF: 0.000237

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	0.087
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.59	N
PhyloP100		0.39
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.079
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.075
MVP		0.055
MPC		0.10
ClinPred		0.065	T
GERP RS		0.53
Varity_R		0.057
gMVP		0.21
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

dbSNP: rs200171139; hg19: chr19-58290301;