Variant 19-2877515-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024967.3(ZNF556):c.557G>A(p.Arg186His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,614,002 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000088 ( 1 hom. )

Consequence

ZNF556
NM_024967.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0310

Variant links:

Genes affected

ZNF556 (HGNC:25669): (zinc finger protein 556) 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]

ZNF556 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017772973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZNF556	NM_024967.3 linkuse as main transcript	c.557G>A	p.Arg186His	missense_variant	4/4	ENST00000307635.3	NP_079243.1
ZNF556	NM_001300843.2 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	4/4		NP_001287772.1
ZNF556	NR_145838.2 linkuse as main transcript	n.640G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF556	ENST00000307635.3 linkuse as main transcript	c.557G>A	p.Arg186His	missense_variant	4/4	2	NM_024967.3	ENSP00000302603	A2
ZNF556	ENST00000586426.5 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	4/4	1		ENSP00000467366	P2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251382

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000125

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000311

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2024

The c.557G>A (p.R186H) alteration is located in exon 4 (coding exon 4) of the ZNF556 gene. This alteration results from a G to A substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0016

.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0

LIST_S2

Benign

0.34

T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.98

.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

1.2

.;N

REVEL

Benign

0.043

Sift

Benign

0.54

.;T

Sift4G

Benign

0.54

T;T

Polyphen

0.74

.;P

Vest4

0.085

MutPred

0.46

.;Loss of MoRF binding (P = 0.0191);

MVP

0.085

MPC

0.051

ClinPred

0.011

GERP RS

1.1

Varity_R

0.041

gMVP

0.029

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over