chr19-8812050-C-T

Variant names:

• chr19-8812050-C-T
• rs147518358
• NM_144693.3:c.440G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_144693.3(ZNF558):​c.440G>A​(p.Arg147His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,585,238 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: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ZNF558 NM_144693.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.543
• Publications: 2 publications found

Genes affected

ZNF558 (HGNC:26422): (zinc finger protein 558) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03133914).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144693.3. 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
	ZNF558	NM_144693.3	MANE Select	c.440G>A	p.Arg147His	missense	Exon 10 of 10	NP_653294.1	Q96NG5-1
	ZNF558	NM_001304350.2		c.227G>A	p.Arg76His	missense	Exon 5 of 5	NP_001291279.1	Q96NG5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF558	ENST00000601372.6	TSL:2 MANE Select	c.440G>A	p.Arg147His	missense	Exon 10 of 10	ENSP00000471277.1	Q96NG5-1
	ZNF558	ENST00000301475.1	TSL:1	c.440G>A	p.Arg147His	missense	Exon 6 of 6	ENSP00000301475.1	Q96NG5-1
	ZNF558	ENST00000869419.1		c.440G>A	p.Arg147His	missense	Exon 10 of 10	ENSP00000539478.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152154 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000805 AC: 18 AN: 223472 AF XY: 0.0000664

Gnomad AFR exome AF: 0.000322

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: 0.0000680

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 168 AN: 1433084 Hom.: 0 Cov.: 30 AF XY: 0.000101 AC XY: 72 AN XY: 709784

African (AFR) AF: 0.000215 AC: 7 AN: 32536

American (AMR) AF: 0.00 AC: 0 AN: 40794

Ashkenazi Jewish (ASJ) AF: 0.0000413 AC: 1 AN: 24238

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.000136 AC: 11 AN: 81178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52362

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5624

European-Non Finnish (NFE) AF: 0.000133 AC: 146 AN: 1097670

Other (OTH) AF: 0.0000338 AC: 2 AN: 59236

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74316

African (AFR) AF: 0.000145 AC: 6 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.095
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00050	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.54
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.044
Sift	Benign	0.31	T
Sift4G	Benign	0.078	T
Polyphen		0.0010	B
Vest4		0.012
MVP		0.24
MPC		0.25
ClinPred		0.042	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.12
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: rs147518358; hg19: chr19-8922726; COSMIC: COSV104619657;