8-28349134-C-T

Variant summary

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

The NM_018660.3(ZNF395):​c.1421G>A​(p.Ser474Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,415,716 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: not found (cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ZNF395
NM_018660.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46
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]

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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=0.117357224).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF395NM_018660.3 linkc.1421G>A p.Ser474Asn missense_variant 9/10 ENST00000344423.10 NP_061130.1 Q9H8N7Q7L9C8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF395ENST00000344423.10 linkc.1421G>A p.Ser474Asn missense_variant 9/101 NM_018660.3 ENSP00000340494.5 Q9H8N7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000283
AC:
4
AN:
1415716
Hom.:
0
Cov.:
31
AF XY:
0.00000286
AC XY:
2
AN XY:
700216
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000544
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000192
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
Cov.:
32

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 GeneticsJan 16, 2024The c.1421G>A (p.S474N) alteration is located in exon 9 (coding exon 8) of the ZNF395 gene. This alteration results from a G to A substitution at nucleotide position 1421, causing the serine (S) at amino acid position 474 to be replaced by an asparagine (N). 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
0.11
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.033
T;T;T
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.025
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.72
.;.;T
M_CAP
Benign
0.0080
T
MetaRNN
Benign
0.12
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;L;L
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.0
N;N;N
REVEL
Benign
0.024
Sift
Benign
0.40
T;T;T
Sift4G
Benign
0.50
T;T;T
Polyphen
0.11
B;B;B
Vest4
0.41
MutPred
0.28
Loss of glycosylation at S474 (P = 0.0076);Loss of glycosylation at S474 (P = 0.0076);Loss of glycosylation at S474 (P = 0.0076);
MVP
0.11
MPC
0.30
ClinPred
0.45
T
GERP RS
4.7
Varity_R
0.079
gMVP
0.26

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: chr8-28206651; API