3-44446799-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_181489.6(ZNF445):​c.2872G>A​(p.Ala958Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ZNF445
NM_181489.6 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.908
Variant links:
Genes affected
ZNF445 (HGNC:21018): (zinc finger protein 445) Enables double-stranded methylated DNA binding activity. Involved in maintenance of DNA methylation and regulation of genetic imprinting. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.045945734).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF445NM_181489.6 linkc.2872G>A p.Ala958Thr missense_variant Exon 8 of 8 ENST00000396077.8 NP_852466.1 P59923
ZNF445NM_001369454.1 linkc.2836G>A p.Ala946Thr missense_variant Exon 7 of 7 NP_001356383.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF445ENST00000396077.8 linkc.2872G>A p.Ala958Thr missense_variant Exon 8 of 8 1 NM_181489.6 ENSP00000379387.2 P59923
ZNF445ENST00000425708.6 linkc.2872G>A p.Ala958Thr missense_variant Exon 6 of 6 1 ENSP00000413073.2 P59923

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251268
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135796
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461876
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727242
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000113
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 04, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2872G>A (p.A958T) alteration is located in exon 8 (coding exon 6) of the ZNF445 gene. This alteration results from a G to A substitution at nucleotide position 2872, causing the alanine (A) at amino acid position 958 to be replaced by a threonine (T). 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
0.087
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.86
CADD
Benign
0.77
DANN
Benign
0.072
DEOGEN2
Benign
0.031
T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.0075
N
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.046
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.34
N;N
PrimateAI
Benign
0.19
T
PROVEAN
Benign
-0.77
N;N
REVEL
Benign
0.028
Sift
Benign
0.55
T;T
Sift4G
Benign
0.59
T;T
Polyphen
0.0020
B;B
Vest4
0.022
MutPred
0.14
Gain of glycosylation at S962 (P = 0.0306);Gain of glycosylation at S962 (P = 0.0306);
MVP
0.13
MPC
0.52
ClinPred
0.074
T
GERP RS
-0.95
Varity_R
0.017
gMVP
0.069

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: rs1035992717; hg19: chr3-44488291; API