1-200407074-C-T

Variant summary

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

The NM_001281293.2(ZNF281):​c.2632G>A​(p.Val878Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZNF281
NM_001281293.2 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.71
Variant links:
Genes affected
ZNF281 (HGNC:13075): (zinc finger protein 281) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in negative regulation of gene expression; negative regulation of transcription by RNA polymerase II; and positive regulation of transcription, DNA-templated. Located in 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=0.23431134).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF281NM_001281293.2 linkc.2632G>A p.Val878Ile missense_variant Exon 2 of 2 ENST00000367353.2 NP_001268222.1 Q9Y2X9-1
ZNF281NM_012482.5 linkc.2632G>A p.Val878Ile missense_variant Exon 2 of 2 NP_036614.1 Q9Y2X9-1
ZNF281NM_001281294.2 linkc.2524G>A p.Val842Ile missense_variant Exon 3 of 3 NP_001268223.1 Q9Y2X9-2B3KMX4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF281ENST00000367353.2 linkc.2632G>A p.Val878Ile missense_variant Exon 2 of 2 1 NM_001281293.2 ENSP00000356322.1 Q9Y2X9-1
ZNF281ENST00000294740.3 linkc.2632G>A p.Val878Ile missense_variant Exon 2 of 2 1 ENSP00000294740.2 Q9Y2X9-1
ZNF281ENST00000367352.3 linkc.2524G>A p.Val842Ile missense_variant Exon 3 of 3 2 ENSP00000356321.3 Q9Y2X9-2
ENSG00000230623ENST00000637430.1 linkn.484+43546C>T intron_variant Intron 4 of 5 5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251316
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135836
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461810
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 21, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2632G>A (p.V878I) alteration is located in exon 2 (coding exon 1) of the ZNF281 gene. This alteration results from a G to A substitution at nucleotide position 2632, causing the valine (V) at amino acid position 878 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
0.12
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.46
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T;T;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.79
.;T;T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.23
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;L;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.43
N;N;N
REVEL
Benign
0.21
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.025
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.39
MutPred
0.12
Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;
MVP
0.16
MPC
1.3
ClinPred
0.62
D
GERP RS
5.6
Varity_R
0.27
gMVP
0.36

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: rs764700174; hg19: chr1-200376202; API