dbSNP rs2088211687: ZNF682:p.Thr497Pro (chr19-20006013-T-G) – 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_033196.3(ZNF682):c.1489A>C(p.Thr497Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,421,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZNF682
NM_033196.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.487

Variant links:

Genes affected

ZNF682 (HGNC:28857): (zinc finger protein 682) 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, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF682 links:

BNIP3P12 (HGNC:49692):

BNIP3P12 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=0.1997917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF682	NM_033196.3 link	c.1489A>C	p.Thr497Pro	missense_variant	Exon 4 of 4	ENST00000397165.7	NP_149973.1	O95780-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF682	ENST00000397165.7 link	c.1489A>C	p.Thr497Pro	missense_variant	Exon 4 of 4	2	NM_033196.3	ENSP00000380351.1		O95780-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1421266

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

702658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31594

American (AMR)

AF:

0.00

AC:

AN:

37298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24460

East Asian (EAS)

AF:

0.00

AC:

AN:

39116

South Asian (SAS)

AF:

0.00

AC:

AN:

80202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1092326

Other (OTH)

AF:

0.00

AC:

AN:

58488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000471

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1489A>C (p.T497P) alteration is located in exon 4 (coding exon 4) of the ZNF682 gene. This alteration results from a A to C substitution at nucleotide position 1489, causing the threonine (T) at amino acid position 497 to be replaced by a proline (P). 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

Benign

0.078

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.043

.;T;.;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.26

T;T;.;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Pathogenic

3.3

.;M;.;.;.

PhyloP100

-0.49

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.9

D;D;D;.;.

REVEL

Benign

0.031

Sift

Uncertain

0.0010

D;D;D;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

0.97

.;D;.;.;.

Vest4

0.084

MutPred

0.26

.;Loss of glycosylation at T497 (P = 0.0631);.;.;.;

MVP

0.77

MPC

0.071

ClinPred

0.45

GERP RS

1.1

Varity_R

0.34

gMVP

0.025

Mutation Taster

=98/2

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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rs2088211687

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over