Genetic Variant NM_144976.4:c.1583A>C (chr19-12526525-T-G) – 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_144976.4(ZNF564):c.1583A>C(p.Asn528Thr) 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 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. N528S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZNF564
NM_144976.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.71

Publications

0 publications found

Variant links:

Genes affected

ZNF564 (HGNC:31106): (zinc finger protein 564) Predicted to enable DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF564 links:

ENSG00000269693 (HGNC:):

ENSG00000269693 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=0.018099695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF564	NM_144976.4 link	c.1583A>C	p.Asn528Thr	missense_variant	Exon 4 of 4	ENST00000339282.12	NP_659413.1	Q8TBZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF564	ENST00000339282.12 link	c.1583A>C	p.Asn528Thr	missense_variant	Exon 4 of 4	1	NM_144976.4	ENSP00000340004.6	Q8TBZ8
ENSG00000269693	ENST00000593682.1 link	n.*4561A>C		non_coding_transcript_exon_variant	Exon 4 of 4	1		ENSP00000473043.1	M0R378
ENSG00000269693	ENST00000593682.1 link	n.*4561A>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000473043.1	M0R378
ENSG00000196826	ENST00000428311.1 link	c.3+24805A>C		intron_variant	Intron 1 of 3	2		ENSP00000404127.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726896

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:

33414

American (AMR)

AF:

0.00

AC:

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111836

Other (OTH)

AF:

0.00

AC:

AN:

60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

0.079

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.13

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.0074

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0

LIST_S2

Benign

0.18

M_CAP

Benign

0.0022

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-2.1

PhyloP100

-1.7

PROVEAN

Benign

2.2

REVEL

Benign

0.036

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.084

MutPred

0.39

Gain of phosphorylation at N528 (P = 0.0187);

MVP

0.055

MPC

0.16

ClinPred

0.046

GERP RS

-3.4

Varity_R

0.034

gMVP

0.013

Mutation Taster

=97/3

polymorphism

(source)

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

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NM_144976.4:c.1583A>C

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