Genetic Variant ZNF653:p.Cys396Tyr (chr19-11487143-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_138783.4(ZNF653):c.1187G>A(p.Cys396Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ZNF653
NM_138783.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.113

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036120772).

BP6

Variant 19-11487143-C-T is Benign according to our data. Variant chr19-11487143-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2302358.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF653	NM_138783.4 link	c.1187G>A	p.Cys396Tyr	missense_variant	Exon 5 of 9	ENST00000293771.10	NP_620138.2	Q96CK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF653	ENST00000293771.10 link	c.1187G>A	p.Cys396Tyr	missense_variant	Exon 5 of 9	1	NM_138783.4	ENSP00000293771.3	Q96CK0
ENSG00000267477	ENST00000585656.1 link	n.469+8807G>A		intron_variant	Intron 3 of 4	5		ENSP00000466387.1	K7EM74
ZNF653	ENST00000592756.1 link	c.20G>A	p.Cys7Tyr	missense_variant	Exon 2 of 5	3		ENSP00000467069.1	K7ENS4
ZNF653	ENST00000590548.5 link	n.1355G>A		non_coding_transcript_exon_variant	Exon 4 of 8	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 19, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.55

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.019

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0020

LIST_S2

Benign

0.61

M_CAP

Benign

0.0018

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.26

PhyloP100

-0.11

PrimateAI

Benign

0.44

PROVEAN

Benign

0.20

REVEL

Benign

0.019

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.20

MutPred

0.32

Loss of catalytic residue at L397 (P = 0.0139);

MVP

0.14

MPC

0.31

ClinPred

0.020

GERP RS

1.1

PromoterAI

-0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.032

gMVP

0.36

Mutation Taster

=99/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over