Genetic Variant ZNF652:p.Val253Ala (chr17-49316968-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001145365.3(ZNF652):c.758T>C(p.Val253Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZNF652
NM_001145365.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Publications

0 publications found

Variant links:

Genes affected

ZNF652 (HGNC:29147): (zinc finger protein 652) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific 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 active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF652 links:

FLJ40194 (HGNC:):

FLJ40194 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF652	NM_001145365.3 link	c.758T>C	p.Val253Ala	missense_variant	Exon 2 of 6	ENST00000430262.3	NP_001138837.1	Q9Y2D9A8K9F2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF652	ENST00000430262.3 link	c.758T>C	p.Val253Ala	missense_variant	Exon 2 of 6	1	NM_001145365.3	ENSP00000416305.2	Q9Y2D9
ZNF652	ENST00000362063.6 link	c.758T>C	p.Val253Ala	missense_variant	Exon 2 of 6	1		ENSP00000354686.2	Q9Y2D9
ZNF652	ENST00000508237.5 link	n.360+398T>C		intron_variant	Intron 3 of 7	2		ENSP00000424848.1	D6RF85
FLJ40194	ENST00000655089.1 link	n.864-623A>G		intron_variant	Intron 4 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.758T>C (p.V253A) alteration is located in exon 2 (coding exon 1) of the ZNF652 gene. This alteration results from a T to C substitution at nucleotide position 758, causing the valine (V) at amino acid position 253 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

T;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

.;D

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.10

N;N

PhyloP100

9.3

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.37

Sift

Benign

0.070

T;T

Sift4G

Benign

0.11

T;T

Polyphen

1.0

D;D

Vest4

0.71

MutPred

0.36

Loss of stability (P = 0.0408);Loss of stability (P = 0.0408);

MVP

0.068

MPC

1.3

ClinPred

0.98

GERP RS

5.6

Varity_R

0.27

gMVP

0.38

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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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