6-57133072-C-T

Variant names:

• chr6-57133072-C-T
• NM_001031623.3:c.455C>T

Variant summary

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

The NM_001031623.3(ZNF451):​c.455C>T​(p.Thr152Ile) 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 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF451 NM_001031623.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.595

Genes affected

ZNF451 (HGNC:21091): (zinc finger protein 451) Enables SUMO ligase activity and transcription corepressor activity. Involved in negative regulation of nitrogen compound metabolic process; negative regulation of transforming growth factor beta receptor signaling pathway; and protein sumoylation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF451-AS1 (HGNC:53824): (ZNF451 regulatory antisense RNA 1)

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=0.27543777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF451	NM_001031623.3	c.455C>T	p.Thr152Ile	missense_variant	Exon 6 of 15	ENST00000370706.9	NP_001026794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF451	ENST00000370706.9	c.455C>T	p.Thr152Ile	missense_variant	Exon 6 of 15	1	NM_001031623.3	ENSP00000359740.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.455C>T (p.T152I) alteration is located in exon 6 (coding exon 6) of the ZNF451 gene. This alteration results from a C to T substitution at nucleotide position 455, causing the threonine (T) at amino acid position 152 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	.;T;T;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	.;.;L;L;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.4	D;D;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.045	D;T;T;T;T
Sift4G	Uncertain	0.023	D;T;T;T;T
Polyphen		0.90, 0.94, 0.82	.;.;P;P;P
Vest4		0.19, 0.20, 0.19
MutPred		0.64		.;.;Loss of catalytic residue at T152 (P = 0.0188);Loss of catalytic residue at T152 (P = 0.0188);Loss of catalytic residue at T152 (P = 0.0188);
MVP		0.39
MPC		0.33
ClinPred		0.93	D
GERP RS		4.2
Varity_R		0.062
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: chr6-56997870;