8-28351727-G-C

Position:

• chr8-28351727-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018660.3(ZNF395):​c.1001C>G​(p.Ala334Gly) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF395 NM_018660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.819

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09806818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF395	NM_018660.3	c.1001C>G	p.Ala334Gly	missense_variant	7/10	ENST00000344423.10	NP_061130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF395	ENST00000344423.10	c.1001C>G	p.Ala334Gly	missense_variant	7/10	1	NM_018660.3	ENSP00000340494	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Aug 22, 2023

The c.1001C>G (p.A334G) alteration is located in exon 7 (coding exon 6) of the ZNF395 gene. This alteration results from a C to G substitution at nucleotide position 1001, causing the alanine (A) at amino acid position 334 to be replaced by a glycine (G). 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	0.090
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.36	.;.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.019	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.29	B;B;B
Vest4		0.25
MutPred		0.33		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.17
MPC		0.33
ClinPred		0.12	T
GERP RS		1.8
Varity_R		0.052
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr8-28209244;