Genetic Variant ZNF836:p.Thr745Ala (chr19-52155450-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001102657.3(ZNF836):c.2233A>G(p.Thr745Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,790 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: 0.0000027 ( 0 hom. )

Consequence

ZNF836
NM_001102657.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69

Variant links:

Genes affected

ZNF836 (HGNC:34333): (zinc finger protein 836) Predicted to enable DNA-binding transcription activator 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]

ZNF836 links:

ENSG00000267827 (HGNC:):

ENSG00000267827 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26992285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF836	NM_001102657.3 link	c.2233A>G	p.Thr745Ala	missense_variant	Exon 5 of 5	ENST00000682614.1	NP_001096127.1	Q6ZNA1
ZNF836	XM_011526558.4 link	c.2233A>G	p.Thr745Ala	missense_variant	Exon 5 of 5		XP_011524860.1	Q6ZNA1
ZNF836	XM_011526559.4 link	c.2233A>G	p.Thr745Ala	missense_variant	Exon 4 of 4		XP_011524861.1	Q6ZNA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF836	ENST00000682614.1 link	c.2233A>G	p.Thr745Ala	missense_variant	Exon 5 of 5		NM_001102657.3	ENSP00000507838.1	Q6ZNA1
ZNF836	ENST00000597252.5 link	c.2233A>G	p.Thr745Ala	missense_variant	Exon 5 of 5	2		ENSP00000470239.1	Q6ZNA1
ENSG00000267827	ENST00000594362.1 link	n.554+5015A>G		intron_variant	Intron 4 of 4	5
ENSG00000267827	ENST00000598982.5 link	n.494+5015A>G		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727196

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:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111932

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

Mar 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2233A>G (p.T745A) alteration is located in exon 5 (coding exon 3) of the ZNF836 gene. This alteration results from a A to G substitution at nucleotide position 2233, causing the threonine (T) at amino acid position 745 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

Benign

0.19

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.23

T;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.

PhyloP100

1.7

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.0

.;D

REVEL

Benign

0.071

Sift

Benign

0.048

.;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.92

P;.

Vest4

0.060

MutPred

0.52

Loss of phosphorylation at T745 (P = 0.0283);Loss of phosphorylation at T745 (P = 0.0283);

MVP

0.24

MPC

0.45

ClinPred

0.94

GERP RS

2.1

Varity_R

0.11

gMVP

0.032

Mutation Taster

=92/8

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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19-52155450-T-C

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