Genetic Variant ZNF556:p.Arg122Leu (chr19-2877323-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024967.3(ZNF556):c.365G>T(p.Arg122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,808 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ZNF556
NM_024967.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.170

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056272656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ZNF556	NM_024967.3 link	c.365G>T	p.Arg122Leu	missense_variant	Exon 4 of 4	ENST00000307635.3	NP_079243.1
ZNF556	NM_001300843.2 link	c.362G>T	p.Arg121Leu	missense_variant	Exon 4 of 4		NP_001287772.1
ZNF556	NR_145838.2 link	n.448G>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF556	ENST00000307635.3 link	c.365G>T	p.Arg122Leu	missense_variant	Exon 4 of 4	2	NM_024967.3	ENSP00000302603.2	Q9HAH1
ZNF556	ENST00000586426.5 link	c.362G>T	p.Arg121Leu	missense_variant	Exon 4 of 4	1		ENSP00000467366.1	A0A0C4DGQ3
ZNF556	ENST00000586470.5 link	n.*151G>T		non_coding_transcript_exon_variant	Exon 4 of 4	3		ENSP00000465533.1	K7EKA5
ZNF556	ENST00000586470.5 link	n.*151G>T		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000465533.1	K7EKA5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251356

AF XY:

0.00000736

show subpopulations

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111958

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.35

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0017

.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0

LIST_S2

Benign

0.37

T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

.;N

PhyloP100

0.17

PrimateAI

Benign

0.21

PROVEAN

Benign

1.4

.;N

REVEL

Benign

0.082

Sift

Benign

0.59

.;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0090

.;B

Vest4

0.17

MutPred

0.40

.;Gain of glycosylation at K121 (P = 0.1023);

MVP

0.030

MPC

0.051

ClinPred

0.052

GERP RS

-4.5

Varity_R

0.040

gMVP

0.026

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over