Genetic Variant ZNF396:p.Glu255Lys (chr18-35369460-C-T) – 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_001322286.2(ZNF396):c.763G>A(p.Glu255Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ZNF396
NM_001322286.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.264

Variant links:

Genes affected

ZNF396 (HGNC:18824): (zinc finger protein 396) Enables protein heterodimerization activity; protein homodimerization activity; and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transcription, DNA-templated. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF396 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=0.12223497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF396	NM_001322286.2 link	c.763G>A	p.Glu255Lys	missense_variant	Exon 4 of 4	ENST00000589332.7	NP_001309215.1	Q96N95-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF396	ENST00000589332.7 link	c.763G>A	p.Glu255Lys	missense_variant	Exon 4 of 4	1	NM_001322286.2	ENSP00000466500.1		Q96N95-1
ZNF396	ENST00000306346.5 link	c.763G>A	p.Glu255Lys	missense_variant	Exon 4 of 5	1		ENSP00000302310.1		Q96N95-3

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251478

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.763G>A (p.E255K) alteration is located in exon 4 (coding exon 3) of the ZNF396 gene. This alteration results from a G to A substitution at nucleotide position 763, causing the glutamic acid (E) at amino acid position 255 to be replaced by a lysine (K). 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

-0.44

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.11

T;T

M_CAP

Benign

0.0096

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.3

D;.

REVEL

Benign

0.051

Sift

Uncertain

0.015

D;.

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.87

P;.

Vest4

0.23

MVP

0.28

MPC

0.14

ClinPred

0.40

GERP RS

0.17

Varity_R

0.15

gMVP

0.11

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