Genetic Variant ZNF251:p.Arg444Gln (chr8-144722329-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138367.2(ZNF251):c.1331G>A(p.Arg444Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ZNF251
NM_138367.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.88

Variant links:

Genes affected

ZNF251 (HGNC:13045): (zinc finger protein 251) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within hematopoietic stem cell homeostasis. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF251 links:

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ACMG classification

Classification made for transcript

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=0.06380385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF251	NM_138367.2 link	c.1331G>A	p.Arg444Gln	missense_variant	Exon 5 of 5	ENST00000292562.12	NP_612376.1	Q9BRH9
ZNF251	XM_024447324.2 link	c.1331G>A	p.Arg444Gln	missense_variant	Exon 5 of 5		XP_024303092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF251	ENST00000292562.12 link	c.1331G>A	p.Arg444Gln	missense_variant	Exon 5 of 5	2	NM_138367.2	ENSP00000292562.7		Q9BRH9
ZNF251	ENST00000524394.2 link	n.200-1307G>A		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250068

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.0000643

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461442

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1331G>A (p.R444Q) alteration is located in exon 5 (coding exon 4) of the ZNF251 gene. This alteration results from a G to A substitution at nucleotide position 1331, causing the arginine (R) at amino acid position 444 to be replaced by a glutamine (Q). 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

0.65

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0093

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.33

M_CAP

Benign

0.0012

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.24

PrimateAI

Benign

0.36

PROVEAN

Benign

0.43

REVEL

Benign

0.050

Sift

Benign

0.60

Sift4G

Benign

0.81

Polyphen

0.74

Vest4

0.087

MutPred

0.41

Loss of MoRF binding (P = 0.0392);

MVP

0.23

MPC

0.33

ClinPred

0.073

GERP RS

2.1

Varity_R

0.014

gMVP

0.038

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