Genetic Variant ZNF836:p.Pro693Leu (chr19-52155605-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001102657.3(ZNF836):c.2078C>T(p.Pro693Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.000019 ( 0 hom. )

Consequence

ZNF836
NM_001102657.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25312093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF836	NM_001102657.3 link	c.2078C>T	p.Pro693Leu	missense_variant	Exon 5 of 5	ENST00000682614.1	NP_001096127.1	Q6ZNA1
ZNF836	XM_011526558.4 link	c.2078C>T	p.Pro693Leu	missense_variant	Exon 5 of 5		XP_011524860.1	Q6ZNA1
ZNF836	XM_011526559.4 link	c.2078C>T	p.Pro693Leu	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.2078C>T	p.Pro693Leu	missense_variant	Exon 5 of 5		NM_001102657.3	ENSP00000507838.1	Q6ZNA1
ZNF836	ENST00000597252.5 link	c.2078C>T	p.Pro693Leu	missense_variant	Exon 5 of 5	2		ENSP00000470239.1	Q6ZNA1
ENSG00000267827	ENST00000594362.1 link	n.554+4860C>T		intron_variant	Intron 4 of 4	5
ENSG00000267827	ENST00000598982.5 link	n.494+4860C>T		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249816

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135498

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2078C>T (p.P693L) alteration is located in exon 5 (coding exon 3) of the ZNF836 gene. This alteration results from a C to T substitution at nucleotide position 2078, causing the proline (P) at amino acid position 693 to be replaced by a leucine (L). 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

0.29

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.20

T;T

M_CAP

Benign

0.0016

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-6.2

.;D

REVEL

Benign

0.044

Sift

Benign

0.031

.;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.79

P;.

Vest4

0.20

MutPred

0.57

Gain of ubiquitination at K692 (P = 0.0609);Gain of ubiquitination at K692 (P = 0.0609);

MVP

0.29

MPC

0.19

ClinPred

0.33

GERP RS

1.2

Varity_R

0.15

gMVP

0.025

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over