1-23362408-C-T

Variant summary

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

The NM_001077195.2(ZNF436):​c.974G>A​(p.Arg325His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,612,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

ZNF436
NM_001077195.2 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.241
Variant links:
Genes affected
ZNF436 (HGNC:20814): (zinc finger protein 436) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.11473474).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF436NM_001077195.2 linkc.974G>A p.Arg325His missense_variant 4/4 ENST00000314011.9 NP_001070663.1 Q9C0F3
ZNF436NM_030634.3 linkc.974G>A p.Arg325His missense_variant 3/3 NP_085137.1 Q9C0F3
ZNF436NM_001370652.1 linkc.920G>A p.Arg307His missense_variant 3/3 NP_001357581.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF436ENST00000314011.9 linkc.974G>A p.Arg325His missense_variant 4/41 NM_001077195.2 ENSP00000313582.4 Q9C0F3
ZNF436ENST00000374608.3 linkc.974G>A p.Arg325His missense_variant 3/31 ENSP00000363736.3 Q9C0F3

Frequencies

GnomAD3 genomes
AF:
0.0000663
AC:
10
AN:
150864
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000488
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000660
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:
0.0000886
Gnomad OTH
AF:
0.000485
GnomAD3 exomes
AF:
0.0000955
AC:
24
AN:
251388
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000968
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000718
AC:
105
AN:
1461660
Hom.:
0
Cov.:
29
AF XY:
0.0000701
AC XY:
51
AN XY:
727140
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000791
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000663
AC:
10
AN:
150864
Hom.:
0
Cov.:
33
AF XY:
0.0000814
AC XY:
6
AN XY:
73674
show subpopulations
Gnomad4 AFR
AF:
0.0000488
Gnomad4 AMR
AF:
0.0000660
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000886
Gnomad4 OTH
AF:
0.000485
Alfa
AF:
0.000205
Hom.:
0
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 GeneticsAug 01, 2024The c.974G>A (p.R325H) alteration is located in exon 4 (coding exon 3) of the ZNF436 gene. This alteration results from a G to A substitution at nucleotide position 974, causing the arginine (R) at amino acid position 325 to be replaced by a histidine (H). 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
0.18
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.032
T;T
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.0017
N
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L;L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.5
N;N
REVEL
Benign
0.069
Sift
Benign
0.20
T;T
Sift4G
Benign
0.069
T;T
Polyphen
0.15
B;B
Vest4
0.10
MVP
0.48
MPC
0.87
ClinPred
0.089
T
GERP RS
3.8
Varity_R
0.071
gMVP
0.17

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: rs377608060; hg19: chr1-23688901; API