6-57134802-T-G

Variant summary

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

The NM_001031623.3(ZNF451):c.634T>G(p.Phe212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 2.24

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=0.3585944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF451	NM_001031623.3	c.634T>G	p.Phe212Val	missense_variant	7/15	ENST00000370706.9
ZNF451-AS1	NR_110742.1	n.235-19239A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF451	ENST00000370706.9	c.634T>G	p.Phe212Val	missense_variant	7/15	1	NM_001031623.3	P2
ZNF451-AS1	ENST00000416069.6	n.444-19239A>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460708 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726720

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 15, 2022

The c.634T>G (p.F212V) alteration is located in exon 7 (coding exon 7) of the ZNF451 gene. This alteration results from a T to G substitution at nucleotide position 634, causing the phenylalanine (F) at amino acid position 212 to be replaced by a valine (V). 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	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.086	T;.;T
Eigen	Benign	-0.043
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.083	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.16	B;P;P
Vest4		0.43
MutPred		0.79		Loss of stability (P = 0.1862);Loss of stability (P = 0.1862);Loss of stability (P = 0.1862);
MVP		0.44
MPC		0.85
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-56999600;