6-57090269-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001031623.3(ZNF451):c.16T>C(p.Ser6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,914 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: not found (cov: 29)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZNF451 NM_001031623.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.410

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]

ACMG classification

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=0.037341923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF451	NM_001031623.3	c.16T>C	p.Ser6Pro	missense_variant	1/15	ENST00000370706.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF451	ENST00000370706.9	c.16T>C	p.Ser6Pro	missense_variant	1/15	1	NM_001031623.3	P2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244624 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458914 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

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

Aug 28, 2023

The c.16T>C (p.S6P) alteration is located in exon 1 (coding exon 1) of the ZNF451 gene. This alteration results from a T to C substitution at nucleotide position 16, causing the serine (S) at amino acid position 6 to be replaced by a proline (P). 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	0.062
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	16
Dann	Benign	0.92
DEOGEN2	Benign	0.022	T;T;.;.;.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.22	T;T;T;T;T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.037	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.64	N;N;N;N;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.043	D;T;T;T;T;D;T;T
Sift4G	Pathogenic	0.0	D;T;T;T;T;D;T;T
Polyphen		0.0	.;B;B;B;.;.;B;.
Vest4		0.098, 0.085, 0.10, 0.10, 0.19
MutPred		0.18		Loss of phosphorylation at S6 (P = 0.0119);Loss of phosphorylation at S6 (P = 0.0119);Loss of phosphorylation at S6 (P = 0.0119);Loss of phosphorylation at S6 (P = 0.0119);Loss of phosphorylation at S6 (P = 0.0119);Loss of phosphorylation at S6 (P = 0.0119);Loss of phosphorylation at S6 (P = 0.0119);Loss of phosphorylation at S6 (P = 0.0119);
MVP		0.42
MPC		0.23
ClinPred		0.047	T
GERP RS		-4.5
Varity_R		0.098
gMVP		0.091

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: rs1285352102; hg19: chr6-56955067;