8-144722366-G-T

Position:

• chr8-144722366-G-T

Variant summary

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

The NM_138367.2(ZNF251):​c.1294C>A​(p.Pro432Thr) 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: 33)
• Consequence: ZNF251 NM_138367.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.65

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]

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/exons	MANE	Protein	UniProt
ZNF251	NM_138367.2	c.1294C>A	p.Pro432Thr	missense_variant	5/5	ENST00000292562.12	NP_612376.1
ZNF251	XM_024447324.2	c.1294C>A	p.Pro432Thr	missense_variant	5/5		XP_024303092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF251	ENST00000292562.12	c.1294C>A	p.Pro432Thr	missense_variant	5/5	2	NM_138367.2	ENSP00000292562	P1
ZNF251	ENST00000524394.2	n.200-1344C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

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

Nov 30, 2021

The c.1294C>A (p.P432T) alteration is located in exon 5 (coding exon 4) of the ZNF251 gene. This alteration results from a C to A substitution at nucleotide position 1294, causing the proline (P) at amino acid position 432 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	Pathogenic	0.93
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0046	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.52		Loss of catalytic residue at P432 (P = 0.0662);
MVP		0.59
MPC		0.53
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.49
gMVP		0.039

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

Other links and lift over

dbSNP: rs1770323601; hg19: chr8-145947751;