Variant 1-200407473-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001281293.2(ZNF281):c.2233C>T(p.Pro745Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,856 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: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ZNF281
NM_001281293.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.75

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1160191).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF281	NM_001281293.2 linkuse as main transcript	c.2233C>T	p.Pro745Ser	missense_variant	2/2	ENST00000367353.2	NP_001268222.1	Q9Y2X9-1
ZNF281	NM_012482.5 linkuse as main transcript	c.2233C>T	p.Pro745Ser	missense_variant	2/2		NP_036614.1	Q9Y2X9-1
ZNF281	NM_001281294.2 linkuse as main transcript	c.2125C>T	p.Pro709Ser	missense_variant	3/3		NP_001268223.1	Q9Y2X9-2B3KMX4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF281	ENST00000367353.2 linkuse as main transcript	c.2233C>T	p.Pro745Ser	missense_variant	2/2	1	NM_001281293.2	ENSP00000356322.1	Q9Y2X9-1
ZNF281	ENST00000294740.3 linkuse as main transcript	c.2233C>T	p.Pro745Ser	missense_variant	2/2	1		ENSP00000294740.2	Q9Y2X9-1
ZNF281	ENST00000367352.3 linkuse as main transcript	c.2125C>T	p.Pro709Ser	missense_variant	3/3	2		ENSP00000356321.3	Q9Y2X9-2
ENSG00000230623	ENST00000637430.1 linkuse as main transcript	n.484+43945G>A		intron_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251424

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

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:

0.00000616

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

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

Dec 28, 2023

The c.2233C>T (p.P745S) alteration is located in exon 2 (coding exon 1) of the ZNF281 gene. This alteration results from a C to T substitution at nucleotide position 2233, causing the proline (P) at amino acid position 745 to be replaced by a serine (S). 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

Uncertain

0.37

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

T;T;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.048

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.45

T;T;T

Polyphen

0.47

P;P;.

Vest4

0.46

MutPred

0.17

Gain of glycosylation at P745 (P = 0.0237);Gain of glycosylation at P745 (P = 0.0237);.;

MVP

0.17

MPC

0.98

ClinPred

0.35

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.088

gMVP

0.32

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