1-200407236-T-C

Position:

• chr1-200407236-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001281293.2(ZNF281):​c.2470A>G​(p.Thr824Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: ZNF281 NM_001281293.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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]

ENSG00000230623 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03392303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF281	NM_001281293.2	c.2470A>G	p.Thr824Ala	missense_variant	2/2	ENST00000367353.2	NP_001268222.1
ZNF281	NM_012482.5	c.2470A>G	p.Thr824Ala	missense_variant	2/2		NP_036614.1
ZNF281	NM_001281294.2	c.2362A>G	p.Thr788Ala	missense_variant	3/3		NP_001268223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF281	ENST00000367353.2	c.2470A>G	p.Thr824Ala	missense_variant	2/2	1	NM_001281293.2	ENSP00000356322.1
ZNF281	ENST00000294740.3	c.2470A>G	p.Thr824Ala	missense_variant	2/2	1		ENSP00000294740.2
ZNF281	ENST00000367352.3	c.2362A>G	p.Thr788Ala	missense_variant	3/3	2		ENSP00000356321.3
ENSG00000230623	ENST00000637430.1	n.484+43708T>C		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.2470A>G (p.T824A) alteration is located in exon 2 (coding exon 1) of the ZNF281 gene. This alteration results from a A to G substitution at nucleotide position 2470, causing the threonine (T) at amino acid position 824 to be replaced by an alanine (A). 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	0.21
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.62	.;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	N;N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.20	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.039
MutPred		0.065		Loss of glycosylation at T824 (P = 0.0357);Loss of glycosylation at T824 (P = 0.0357);.;
MVP		0.043
MPC		0.50
ClinPred		0.24	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-200376364;