chr1-200407219-C-A

Position:

• chr1-200407219-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000367353.2(ZNF281):​c.2487G>T​(p.Glu829Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 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: 6.8e-7 (0 hom.)
• Consequence: ZNF281 ENST00000367353.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38631803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF281	NM_001281293.2	c.2487G>T	p.Glu829Asp	missense_variant	2/2	ENST00000367353.2	NP_001268222.1
ZNF281	NM_012482.5	c.2487G>T	p.Glu829Asp	missense_variant	2/2		NP_036614.1
ZNF281	NM_001281294.2	c.2379G>T	p.Glu793Asp	missense_variant	3/3		NP_001268223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF281	ENST00000367353.2	c.2487G>T	p.Glu829Asp	missense_variant	2/2	1	NM_001281293.2	ENSP00000356322	P2
ZNF281	ENST00000294740.3	c.2487G>T	p.Glu829Asp	missense_variant	2/2	1		ENSP00000294740	P2
	ENST00000637430.1	n.484+43691C>A		intron_variant, non_coding_transcript_variant		5
ZNF281	ENST00000367352.3	c.2379G>T	p.Glu793Asp	missense_variant	3/3	2		ENSP00000356321	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Oct 25, 2022

The c.2487G>T (p.E829D) alteration is located in exon 2 (coding exon 1) of the ZNF281 gene. This alteration results from a G to T substitution at nucleotide position 2487, causing the glutamic acid (E) at amino acid position 829 to be replaced by an aspartic acid (D). 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	Pathogenic	0.83
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.040	D;D;T
Polyphen		1.0	D;D;.
Vest4		0.55
MutPred		0.34		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;
MVP		0.19
MPC		1.3
ClinPred		0.85	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.41

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: chr1-200376347;