8-28359707-C-T

Position:

• chr8-28359707-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018660.3(ZNF395):​c.358G>A​(p.Glu120Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF395 NM_018660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29545367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF395	NM_018660.3	c.358G>A	p.Glu120Lys	missense_variant	3/10	ENST00000344423.10	NP_061130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF395	ENST00000344423.10	c.358G>A	p.Glu120Lys	missense_variant	3/10	1	NM_018660.3	ENSP00000340494	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.358G>A (p.E120K) alteration is located in exon 3 (coding exon 2) of the ZNF395 gene. This alteration results from a G to A substitution at nucleotide position 358, causing the glutamic acid (E) at amino acid position 120 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	0.15
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.86	.;.;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.93	N;N;N;N;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D;D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;.;.;.
Polyphen		0.95	P;P;P;.;.;.
Vest4		0.51
MutPred		0.55		Gain of ubiquitination at E120 (P = 0.0177);Gain of ubiquitination at E120 (P = 0.0177);Gain of ubiquitination at E120 (P = 0.0177);Gain of ubiquitination at E120 (P = 0.0177);Gain of ubiquitination at E120 (P = 0.0177);Gain of ubiquitination at E120 (P = 0.0177);
MVP		0.23
MPC		0.60
ClinPred		0.89	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-28217224;