Genetic Variant ZNF653:p.Glu445Asp (chr19-11486995-C-A) – 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_138783.4(ZNF653):c.1335G>T(p.Glu445Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZNF653
NM_138783.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.812

Publications

0 publications found

Variant links:

Genes affected

ZNF653 (HGNC:25196): (zinc finger protein 653) Enables AF-2 domain binding activity and transcription corepressor activity. Involved in extracellular negative regulation of signal transduction and negative regulation of nucleic acid-templated transcription. Predicted to be located in extracellular region. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF653 links:

ENSG00000267477 (HGNC:):

ENSG00000267477 links:

Genome browser will be placed here

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=0.15807375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF653	NM_138783.4 link	c.1335G>T	p.Glu445Asp	missense_variant	Exon 5 of 9	ENST00000293771.10	NP_620138.2	Q96CK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF653	ENST00000293771.10 link	c.1335G>T	p.Glu445Asp	missense_variant	Exon 5 of 9	1	NM_138783.4	ENSP00000293771.3		Q96CK0
ENSG00000267477	ENST00000585656.1 link	n.469+8955G>T		intron_variant	Intron 3 of 4	5		ENSP00000466387.1		K7EM74

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250608

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000137

AC:

AN:

1461460

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727044

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:

33474

American (AMR)

AF:

0.0000447

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111792

Other (OTH)

AF:

0.00

AC:

AN:

60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Uncertain

0.41

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

Eigen

Benign

-0.12

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

M_CAP

Benign

0.0048

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.81

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.98

REVEL

Benign

0.11

Sift

Uncertain

0.022

Sift4G

Benign

0.22

Polyphen

0.43

Vest4

0.40

MutPred

0.34

Gain of loop (P = 0.0502);

MVP

0.50

MPC

0.72

ClinPred

0.25

GERP RS

4.5

PromoterAI

0.022

Neutral

(source)

Varity_R

0.089

gMVP

0.51

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr19-11486995-C-A

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