Genetic Variant NM_001102657.3:c.1834T>G (chr19-52155849-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001102657.3(ZNF836):c.1834T>G(p.Cys612Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C612R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ZNF836
NM_001102657.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.45

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF836	NM_001102657.3 link	c.1834T>G	p.Cys612Gly	missense_variant	Exon 5 of 5	ENST00000682614.1	NP_001096127.1	Q6ZNA1
ZNF836	XM_011526558.4 link	c.1834T>G	p.Cys612Gly	missense_variant	Exon 5 of 5		XP_011524860.1	Q6ZNA1
ZNF836	XM_011526559.4 link	c.1834T>G	p.Cys612Gly	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.1834T>G	p.Cys612Gly	missense_variant	Exon 5 of 5		NM_001102657.3	ENSP00000507838.1	Q6ZNA1
ZNF836	ENST00000597252.5 link	c.1834T>G	p.Cys612Gly	missense_variant	Exon 5 of 5	2		ENSP00000470239.1	Q6ZNA1
ENSG00000267827	ENST00000594362.1 link	n.554+4616T>G		intron_variant	Intron 4 of 4	5
ENSG00000267827	ENST00000598982.5 link	n.494+4616T>G		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.39

T;.

Eigen

Uncertain

0.44

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.18

T;T

M_CAP

Benign

0.0015

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.086

MutationAssessor

Pathogenic

4.5

H;.

PhyloP100

7.4

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-11

.;D

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.30

MutPred

0.75

Loss of stability (P = 0.0497);Loss of stability (P = 0.0497);

MVP

0.77

MPC

0.67

ClinPred

1.0

GERP RS

2.1

Varity_R

0.88

gMVP

0.15

Mutation Taster

=100/0

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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over