1-200407718-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001281293.2(ZNF281):​c.1988G>A​(p.Ser663Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ZNF281
NM_001281293.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.303
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.036579996).
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF281NM_001281293.2 linkc.1988G>A p.Ser663Asn missense_variant Exon 2 of 2 ENST00000367353.2 NP_001268222.1 Q9Y2X9-1
ZNF281NM_012482.5 linkc.1988G>A p.Ser663Asn missense_variant Exon 2 of 2 NP_036614.1 Q9Y2X9-1
ZNF281NM_001281294.2 linkc.1880G>A p.Ser627Asn 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.1988G>A p.Ser663Asn missense_variant Exon 2 of 2 1 NM_001281293.2 ENSP00000356322.1 Q9Y2X9-1
ZNF281ENST00000294740.3 linkc.1988G>A p.Ser663Asn missense_variant Exon 2 of 2 1 ENSP00000294740.2 Q9Y2X9-1
ZNF281ENST00000367352.3 linkc.1880G>A p.Ser627Asn missense_variant Exon 3 of 3 2 ENSP00000356321.3 Q9Y2X9-2
ENSG00000230623ENST00000637430.1 linkn.484+44190C>T intron_variant Intron 4 of 5 5

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000266
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251382
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.000185
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461840
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.000266
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000100
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 27, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1988G>A (p.S663N) 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 1988, causing the serine (S) at amino acid position 663 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
0.10
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
4.3
DANN
Benign
0.77
DEOGEN2
Benign
0.23
T;T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.61
.;T;T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.037
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.76
N;N;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.71
N;N;N
REVEL
Benign
0.062
Sift
Benign
0.23
T;T;T
Sift4G
Benign
0.14
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.074
MVP
0.082
MPC
0.47
ClinPred
0.0081
T
GERP RS
-0.52
Varity_R
0.057
gMVP
0.20

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: rs371911270; hg19: chr1-200376846; API