Genetic Variant ZNF556:p.Arg122Pro (chr19-2877323-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024967.3(ZNF556):c.365G>C(p.Arg122Pro) 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 1,461,808 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: 6.8e-7 ( 0 hom. )

Consequence

ZNF556
NM_024967.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.170

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.068439454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ZNF556	NM_024967.3 link	c.365G>C	p.Arg122Pro	missense_variant	Exon 4 of 4	ENST00000307635.3	NP_079243.1
ZNF556	NM_001300843.2 link	c.362G>C	p.Arg121Pro	missense_variant	Exon 4 of 4		NP_001287772.1
ZNF556	NR_145838.2 link	n.448G>C		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>C	p.Arg122Pro	missense_variant	Exon 4 of 4	2	NM_024967.3	ENSP00000302603.2	Q9HAH1
ZNF556	ENST00000586426.5 link	c.362G>C	p.Arg121Pro	missense_variant	Exon 4 of 4	1		ENSP00000467366.1	A0A0C4DGQ3
ZNF556	ENST00000586470.5 link	n.*151G>C		non_coding_transcript_exon_variant	Exon 4 of 4	3		ENSP00000465533.1	K7EKA5
ZNF556	ENST00000586470.5 link	n.*151G>C		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000465533.1	K7EKA5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727188

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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:

8.99e-7

AC:

AN:

1111958

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.7

(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

0.33

T;T

M_CAP

Benign

0.0010

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

.;N

PhyloP100

0.17

PrimateAI

Benign

0.21

PROVEAN

Benign

0.19

.;N

REVEL

Benign

0.068

Sift

Benign

0.18

.;T

Sift4G

Benign

0.11

T;T

Polyphen

0.0

.;B

Vest4

0.16

MutPred

0.41

.;Gain of glycosylation at K121 (P = 0.0856);

MVP

0.040

MPC

0.12

ClinPred

0.057

GERP RS

-4.5

Varity_R

0.075

gMVP

0.074

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over