6-57147646-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001031623.3(ZNF451):c.1561C>A(p.His521Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ZNF451 NM_001031623.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF451	NM_001031623.3	c.1561C>A	p.His521Asn	missense_variant	10/15	ENST00000370706.9
ZNF451-AS1	NR_110742.1	n.234+23359G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF451	ENST00000370706.9	c.1561C>A	p.His521Asn	missense_variant	10/15	1	NM_001031623.3	P2
ZNF451-AS1	ENST00000416069.6	n.443+23359G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

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: 0.00

Gnomad4 OTH AF: 0.00

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

Dec 14, 2022

The c.1561C>A (p.H521N) alteration is located in exon 10 (coding exon 10) of the ZNF451 gene. This alteration results from a C to A substitution at nucleotide position 1561, causing the histidine (H) at amino acid position 521 to be replaced by an asparagine (N). 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	0.99
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.8	H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.81
MutPred		0.49		Gain of MoRF binding (P = 0.1498);Gain of MoRF binding (P = 0.1498);Gain of MoRF binding (P = 0.1498);
MVP		0.65
MPC		0.77
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.70

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: rs1233679294; hg19: chr6-57012444; COSMIC: COSV100674996; COSMIC: COSV100674996;