8-28349218-C-T

Variant names:

Variant summary

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

The NM_018660.3(ZNF395):c.1337G>A(p.Arg446Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000388 in 1,545,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ZNF395
NM_018660.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.44

Publications

1 publications found

Variant links:

Genes affected

ZNF395 (HGNC:18737): (zinc finger protein 395) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ZNF395 links:

FBXO16 (HGNC:13618): (F-box protein 16) This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbx class. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

FBXO16 links:

Genome browser will be placed here

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=0.30480182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF395	NM_018660.3 link	c.1337G>A	p.Arg446Gln	missense_variant	Exon 9 of 10	ENST00000344423.10	NP_061130.1	Q9H8N7Q7L9C8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF395	ENST00000344423.10 link	c.1337G>A	p.Arg446Gln	missense_variant	Exon 9 of 10	1	NM_018660.3	ENSP00000340494.5		Q9H8N7

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000307

AC:

AN:

195246

AF XY:

0.0000289

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000652

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000395

AC:

AN:

1393318

Hom.:

Cov.:

AF XY:

0.0000335

AC XY:

AN XY:

686236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31104

American (AMR)

AF:

0.00

AC:

AN:

33844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21880

East Asian (EAS)

AF:

0.00

AC:

AN:

38552

South Asian (SAS)

AF:

0.0000132

AC:

AN:

75628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5450

European-Non Finnish (NFE)

AF:

0.0000491

AC:

AN:

1078552

Other (OTH)

AF:

0.0000175

AC:

AN:

57276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1337G>A (p.R446Q) alteration is located in exon 9 (coding exon 8) of the ZNF395 gene. This alteration results from a G to A substitution at nucleotide position 1337, causing the arginine (R) at amino acid position 446 to be replaced by a glutamine (Q). 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

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.065

T;T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.81

.;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.9

L;L;L

PhyloP100

3.4

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.089

Sift

Benign

0.044

D;D;D

Sift4G

Benign

0.082

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.52

MutPred

0.17

Gain of glycosylation at S447 (P = 0.0787);Gain of glycosylation at S447 (P = 0.0787);Gain of glycosylation at S447 (P = 0.0787);

MVP

0.24

MPC

0.49

ClinPred

0.52

GERP RS

4.6

Varity_R

0.095

gMVP

0.54

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

8-28349218-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over