Genetic Variant ZNF281:p.Ser663Asn (chr1-200407718-C-T) – ACMG Classification: Benign (-8 pts)

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

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]

ZNF281 links:

ENSG00000230623 (HGNC:):

ENSG00000230623 links:

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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
ZNF281	NM_001281293.2 link	c.1988G>A	p.Ser663Asn	missense_variant	Exon 2 of 2	ENST00000367353.2	NP_001268222.1	Q9Y2X9-1
ZNF281	NM_012482.5 link	c.1988G>A	p.Ser663Asn	missense_variant	Exon 2 of 2		NP_036614.1	Q9Y2X9-1
ZNF281	NM_001281294.2 link	c.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	UniProt
ZNF281	ENST00000367353.2 link	c.1988G>A	p.Ser663Asn	missense_variant	Exon 2 of 2	1	NM_001281293.2	ENSP00000356322.1	Q9Y2X9-1
ZNF281	ENST00000294740.3 link	c.1988G>A	p.Ser663Asn	missense_variant	Exon 2 of 2	1		ENSP00000294740.2	Q9Y2X9-1
ZNF281	ENST00000367352.3 link	c.1880G>A	p.Ser627Asn	missense_variant	Exon 3 of 3	2		ENSP00000356321.3	Q9Y2X9-2
ENSG00000230623	ENST00000637430.1 link	n.484+44190C>T		intron_variant	Intron 4 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152162

Hom.:

Cov.:

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:

AN:

251382

Hom.:

AF XY:

0.00000736

AC XY:

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:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

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:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

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.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000165

AC:

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

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

LIST_S2

Benign

0.61

.;T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

N;N;.

PrimateAI

Benign

0.34

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over