NM_022095.4:c.3912T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_022095.4(ZNF335):​c.3912T>A​(p.Asp1304Glu) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ZNF335
NM_022095.4 missense

Scores

3
3
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.116

Publications

0 publications found
Variant links:
Genes affected
ZNF335 (HGNC:15807): (zinc finger protein 335) The protein encoded by this gene enhances transcriptional activation by ligand-bound nuclear hormone receptors. However, it does this not by direct interaction with the receptor, but by direct interaction with the nuclear hormone receptor transcriptional coactivator NRC. The encoded protein may function by altering local chromatin structure. [provided by RefSeq, Jul 2008]
ZNF335 Gene-Disease associations (from GenCC):
  • microcephalic primordial dwarfism due to ZNF335 deficiency
    Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33100528).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF335NM_022095.4 linkc.3912T>A p.Asp1304Glu missense_variant Exon 28 of 28 ENST00000322927.3 NP_071378.1 Q9H4Z2-1Q8IW09
ZNF335XM_047440363.1 linkc.3912T>A p.Asp1304Glu missense_variant Exon 27 of 27 XP_047296319.1
ZNF335XM_005260504.5 linkc.3909T>A p.Asp1303Glu missense_variant Exon 27 of 27 XP_005260561.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF335ENST00000322927.3 linkc.3912T>A p.Asp1304Glu missense_variant Exon 28 of 28 1 NM_022095.4 ENSP00000325326.2 Q9H4Z2-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jun 20, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1304 of the ZNF335 protein (p.Asp1304Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ZNF335-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.77
T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.33
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L
PhyloP100
0.12
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-0.91
N
REVEL
Benign
0.26
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.39
MutPred
0.72
Gain of disorder (P = 0.1018);
MVP
0.38
MPC
0.61
ClinPred
0.85
D
GERP RS
-1.0
Varity_R
0.39
gMVP
0.50
Mutation Taster
=79/21
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1466554079; hg19: chr20-44577709; API