Genetic Variant ZNF395:p.Ser474Asn (chr8-28349134-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018660.3(ZNF395):c.1421G>A(p.Ser474Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,415,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ZNF395
NM_018660.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.117357224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF395	NM_018660.3 link	c.1421G>A	p.Ser474Asn	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.1421G>A	p.Ser474Asn	missense_variant	Exon 9 of 10	1	NM_018660.3	ENSP00000340494.5		Q9H8N7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1415716

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

700216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31792

American (AMR)

AF:

0.0000544

AC:

AN:

36794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23134

East Asian (EAS)

AF:

0.00

AC:

AN:

39214

South Asian (SAS)

AF:

0.00

AC:

AN:

78866

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090038

Other (OTH)

AF:

0.0000172

AC:

AN:

58234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1421G>A (p.S474N) 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 1421, causing the serine (S) at amino acid position 474 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.033

T;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.025

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.72

.;.;T

M_CAP

Benign

0.0080

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L;L

PhyloP100

2.5

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.024

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.50

T;T;T

Polyphen

0.11

B;B;B

Vest4

0.41

MutPred

0.28

Loss of glycosylation at S474 (P = 0.0076);Loss of glycosylation at S474 (P = 0.0076);Loss of glycosylation at S474 (P = 0.0076);

MVP

0.11

MPC

0.30

ClinPred

0.45

GERP RS

4.7

Varity_R

0.079

gMVP

0.26

Mutation Taster

=87/13

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over