ENST00000396150.4:c.221C>T

Variant names:

• chr19-57778935-C-T
• rs776286542
• ENST00000396150.4:c.221C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000396150.4(ZNF586):​c.221C>T​(p.Ala74Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A74S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF586 ENST00000396150.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00900
• Publications: 0 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0450193).
• BP6: Variant 19-57778935-C-T is Benign according to our data. Variant chr19-57778935-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3821938.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396150.4. 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.348C>T	p.Arg116Arg	synonymous	Exon 3 of 3	NP_060122.2	Q9NXT0-1
	ZNF586	NM_001077426.3		c.221C>T	p.Ala74Val	missense	Exon 2 of 2	NP_001070894.1	Q9NXT0-2
	ZNF586	NM_001204814.2		c.219C>T	p.Arg73Arg	synonymous	Exon 4 of 4	NP_001191743.1	Q9NXT0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF586	ENST00000396150.4	TSL:1	c.221C>T	p.Ala74Val	missense	Exon 2 of 2	ENSP00000379454.3	Q9NXT0-2
	ZNF586	ENST00000396154.7	TSL:1 MANE Select	c.348C>T	p.Arg116Arg	synonymous	Exon 3 of 3	ENSP00000379458.1	Q9NXT0-1
	ZNF586	ENST00000391702.3	TSL:2	c.219C>T	p.Arg73Arg	synonymous	Exon 4 of 4	ENSP00000375583.3	Q9NXT0-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250130 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

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	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.70
DANN	Benign	0.37
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.89	T
PhyloP100		0.0090
PROVEAN	Benign	1.7	N
REVEL	Benign	0.0090
Sift	Benign	0.53	T
Vest4		0.096
MutPred		0.43		Loss of ubiquitination at K77 (P = 0.0531)
MVP		0.014
ClinPred		0.028	T
GERP RS		-2.6
Mutation Taster		=90/10	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: rs776286542; hg19: chr19-58290303;