Genetic Variant ZNF251:p.Ala602Thr (chr8-144721856-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.1804G>A(p.Ala602Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000507 in 1,499,490 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

ZNF251
NM_138367.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.36

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:

Genome browser will be placed here

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=0.053447008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF251	NM_138367.2 link	c.1804G>A	p.Ala602Thr	missense_variant	Exon 5 of 5	ENST00000292562.12	NP_612376.1	Q9BRH9
ZNF251	XM_024447324.2 link	c.1804G>A	p.Ala602Thr	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.1804G>A	p.Ala602Thr	missense_variant	Exon 5 of 5	2	NM_138367.2	ENSP00000292562.7		Q9BRH9
ZNF251	ENST00000524394.2 link	n.200-834G>A		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000403

AC:

AN:

173826

Hom.:

AF XY:

0.0000327

AC XY:

AN XY:

91752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000817

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1347342

Hom.:

Cov.:

AF XY:

0.0000532

AC XY:

AN XY:

657548

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000154

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000634

Gnomad4 OTH exome

AF:

0.0000361

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000617

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000342

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1804G>A (p.A602T) 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 1804, causing the alanine (A) at amino acid position 602 to be replaced by a threonine (T). 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

0.087

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.3

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0071

LIST_S2

Benign

0.29

M_CAP

Benign

0.0044

MetaRNN

Benign

0.053

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.18

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

REVEL

Benign

0.022

Sift

Benign

0.22

Sift4G

Benign

0.34

Polyphen

0.26

Vest4

0.045

MVP

0.15

MPC

0.50

ClinPred

0.097

GERP RS

2.0

Varity_R

0.035

gMVP

0.013

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