Variant 19-2876260-A-G 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.298A>G(p.Lys100Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000584 in 1,593,772 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

ZNF556
NM_024967.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.05

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:

ZNF556 (HGNC:):

ZNF556 links:

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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=0.023896724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZNF556	NM_024967.3 linkuse as main transcript	c.298A>G	p.Lys100Glu	missense_variant	3/4	ENST00000307635.3	NP_079243.1
ZNF556	NM_001300843.2 linkuse as main transcript	c.298A>G	p.Lys100Glu	missense_variant	3/4		NP_001287772.1
ZNF556	NR_145838.2 linkuse as main transcript	n.381A>G		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF556	ENST00000307635.3 linkuse as main transcript	c.298A>G	p.Lys100Glu	missense_variant	3/4	2	NM_024967.3	ENSP00000302603.2	Q9HAH1
ZNF556	ENST00000586426.5 linkuse as main transcript	c.298A>G	p.Lys100Glu	missense_variant	3/4	1		ENSP00000467366.1	A0A0C4DGQ3
ZNF556	ENST00000586470.5 linkuse as main transcript	n.*84A>G		non_coding_transcript_exon_variant	3/4	3		ENSP00000465533.1	K7EKA5
ZNF556	ENST00000586470.5 linkuse as main transcript	n.*84A>G		3_prime_UTR_variant	3/4	3		ENSP00000465533.1	K7EKA5

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000569

AC:

AN:

228368

Hom.:

AF XY:

0.0000564

AC XY:

AN XY:

124104

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.0000356

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000298

AC:

AN:

1441622

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

716926

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.0000255

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000504

GnomAD4 genome

AF:

0.000329

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000888

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

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

Feb 21, 2024

The c.298A>G (p.K100E) alteration is located in exon 3 (coding exon 3) of the ZNF556 gene. This alteration results from a A to G substitution at nucleotide position 298, causing the lysine (K) at amino acid position 100 to be replaced by a glutamic acid (E). 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

0.068

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.3

DANN

Benign

0.49

DEOGEN2

Benign

0.0029

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.000040

LIST_S2

Benign

0.27

T;T

M_CAP

Benign

0.00080

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

.;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

0.40

.;N

REVEL

Benign

0.015

Sift

Benign

0.15

.;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0

.;B

Vest4

0.034

MVP

0.10

MPC

0.052

ClinPred

0.025

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.033

gMVP

0.094

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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