8-28348785-G-C

Variant names:

• chr8-28348785-G-C
• rs370570508
• NM_018660.3:c.1476C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018660.3(ZNF395):​c.1476C>G​(p.Ile492Met) 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. 14/22 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: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF395 NM_018660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.73
• Publications: 0 publications found

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

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=0.0830037).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018660.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF395	NM_018660.3	MANE Select	c.1476C>G	p.Ile492Met	missense	Exon 10 of 10	NP_061130.1	Q9H8N7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF395	ENST00000344423.10	TSL:1 MANE Select	c.1476C>G	p.Ile492Met	missense	Exon 10 of 10	ENSP00000340494.5	Q9H8N7
	ZNF395	ENST00000523095.5	TSL:1	c.1476C>G	p.Ile492Met	missense	Exon 10 of 10	ENSP00000428452.1	Q9H8N7
	ZNF395	ENST00000523202.5	TSL:1	c.1476C>G	p.Ile492Met	missense	Exon 10 of 10	ENSP00000429640.1	Q9H8N7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.080	N
PhyloP100		-1.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.20
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Polyphen		0.98	D
Vest4		0.23
MutPred		0.32		Gain of disorder (P = 0.0227)
MVP		0.082
MPC		0.95
ClinPred		0.67	D
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.32
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs370570508; hg19: chr8-28206302;