1-200407632-A-C

Variant names:

• chr1-200407632-A-C
• NM_001281293.2:c.2074T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001281293.2(ZNF281):​c.2074T>G​(p.Phe692Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.03

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF281	NM_001281293.2	c.2074T>G	p.Phe692Val	missense_variant	Exon 2 of 2	ENST00000367353.2	NP_001268222.1
ZNF281	NM_012482.5	c.2074T>G	p.Phe692Val	missense_variant	Exon 2 of 2		NP_036614.1
ZNF281	NM_001281294.2	c.1966T>G	p.Phe656Val	missense_variant	Exon 3 of 3		NP_001268223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF281	ENST00000367353.2	c.2074T>G	p.Phe692Val	missense_variant	Exon 2 of 2	1	NM_001281293.2	ENSP00000356322.1
ZNF281	ENST00000294740.3	c.2074T>G	p.Phe692Val	missense_variant	Exon 2 of 2	1		ENSP00000294740.2
ZNF281	ENST00000367352.3	c.1966T>G	p.Phe656Val	missense_variant	Exon 3 of 3	2		ENSP00000356321.3
ENSG00000230623	ENST00000637430.1	n.484+44104A>C		intron_variant	Intron 4 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2074T>G (p.F692V) alteration is located in exon 2 (coding exon 1) of the ZNF281 gene. This alteration results from a T to G substitution at nucleotide position 2074, causing the phenylalanine (F) at amino acid position 692 to be replaced by a valine (V). 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	0.73
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.037	D;D;D
Polyphen		0.43	B;B;.
Vest4		0.64
MutPred		0.31		Loss of catalytic residue at F692 (P = 0.1412);Loss of catalytic residue at F692 (P = 0.1412);.;
MVP		0.19
MPC		1.6
ClinPred		0.79	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.33

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: chr1-200376760;