8-28351586-T-A

Variant names:

• chr8-28351586-T-A
• rs1265824808
• NM_018660.3:c.1142A>T

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.1142A>T​(p.His381Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H381P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF395 NM_018660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.659
• 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=0.077178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF395	NM_018660.3	c.1142A>T	p.His381Leu	missense_variant	Exon 7 of 10	ENST00000344423.10	NP_061130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF395	ENST00000344423.10	c.1142A>T	p.His381Leu	missense_variant	Exon 7 of 10	1	NM_018660.3	ENSP00000340494.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727048

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1142A>T (p.H381L) alteration is located in exon 7 (coding exon 6) of the ZNF395 gene. This alteration results from a A to T substitution at nucleotide position 1142, causing the histidine (H) at amino acid position 381 to be replaced by a leucine (L). 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	0.069
BayesDel_addAF	Benign	0.0055	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.68
DEOGEN2	Benign	0.058	T;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.60	.;.;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.077	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L;L;L
PhyloP100		0.66
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.72	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.35
MutPred		0.23		Loss of solvent accessibility (P = 0.0087);Loss of solvent accessibility (P = 0.0087);Loss of solvent accessibility (P = 0.0087);
MVP		0.32
MPC		0.43
ClinPred		0.15	T
GERP RS		2.9
PromoterAI		0.18	Neutral
Varity_R		0.050
gMVP		0.29
Mutation Taster		=97/3	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: rs1265824808; hg19: chr8-28209103;