8-28351802-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018660.3(ZNF395):​c.926C>T​(p.Thr309Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000661 in 1,542,900 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

ZNF395
NM_018660.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.19195175).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF395NM_018660.3 linkc.926C>T p.Thr309Ile missense_variant 7/10 ENST00000344423.10 NP_061130.1 Q9H8N7Q7L9C8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF395ENST00000344423.10 linkc.926C>T p.Thr309Ile missense_variant 7/101 NM_018660.3 ENSP00000340494.5 Q9H8N7

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000651
AC:
13
AN:
199762
Hom.:
0
AF XY:
0.0000749
AC XY:
8
AN XY:
106788
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000127
Gnomad OTH exome
AF:
0.000202
GnomAD4 exome
AF:
0.0000676
AC:
94
AN:
1390696
Hom.:
0
Cov.:
31
AF XY:
0.0000731
AC XY:
50
AN XY:
684078
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000816
Gnomad4 OTH exome
AF:
0.0000865
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000120
Hom.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 16, 2024The c.926C>T (p.T309I) alteration is located in exon 7 (coding exon 6) of the ZNF395 gene. This alteration results from a C to T substitution at nucleotide position 926, causing the threonine (T) at amino acid position 309 to be replaced by an isoleucine (I). 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
0.21
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.061
T;T;T
Eigen
Benign
0.16
Eigen_PC
Benign
0.17
FATHMM_MKL
Benign
0.50
D
LIST_S2
Benign
0.66
.;.;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.19
T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.2
L;L;L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.050
Sift
Benign
0.14
T;T;T
Sift4G
Benign
0.19
T;T;T
Polyphen
0.93
P;P;P
Vest4
0.30
MVP
0.10
MPC
0.65
ClinPred
0.13
T
GERP RS
4.1
Varity_R
0.095
gMVP
0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201676081; hg19: chr8-28209319; API