Variant 1-200407658-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000367353.2(ZNF281):c.2048G>A(p.Ser683Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ZNF281
ENST00000367353.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65

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:

(HGNC:):

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=0.052074492).

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZNF281	NM_001281293.2 linkuse as main transcript	c.2048G>A	p.Ser683Asn	missense_variant	2/2	ENST00000367353.2	NP_001268222.1
ZNF281	NM_012482.5 linkuse as main transcript	c.2048G>A	p.Ser683Asn	missense_variant	2/2		NP_036614.1
ZNF281	NM_001281294.2 linkuse as main transcript	c.1940G>A	p.Ser647Asn	missense_variant	3/3		NP_001268223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF281	ENST00000367353.2 linkuse as main transcript	c.2048G>A	p.Ser683Asn	missense_variant	2/2	1	NM_001281293.2	ENSP00000356322	P2	Q9Y2X9-1
ZNF281	ENST00000294740.3 linkuse as main transcript	c.2048G>A	p.Ser683Asn	missense_variant	2/2	1		ENSP00000294740	P2	Q9Y2X9-1
	ENST00000637430.1 linkuse as main transcript	n.484+44130C>T		intron_variant, non_coding_transcript_variant		5
ZNF281	ENST00000367352.3 linkuse as main transcript	c.1940G>A	p.Ser647Asn	missense_variant	3/3	2		ENSP00000356321	A2	Q9Y2X9-2

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000215

AC:

AN:

251450

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.000316

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000190

AC:

278

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

154

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.000210

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000243

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000421

Hom.:

Bravo

AF:

0.000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

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 submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.2048G>A (p.S683N) 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 2048, causing the serine (S) at amino acid position 683 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

0.18

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.65

.;T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

0.97

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.93

N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.023

D;D;D

Polyphen

0.0

B;B;.

Vest4

0.073

MVP

0.082

MPC

0.48

ClinPred

0.072

GERP RS

5.5

Varity_R

0.22

gMVP

0.16

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