5-178964877-C-G

Position:

• chr5-178964877-C-G

Variant summary

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

The NM_001178089.3(ZNF454):​c.473C>G​(p.Thr158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF454 NM_001178089.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00400

Genes affected

ZNF454 (HGNC:21200): (zinc finger protein 454) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active 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=0.048627168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF454	NM_001178089.3	c.473C>G	p.Thr158Ser	missense_variant	5/5	ENST00000519564.2	NP_001171560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF454	ENST00000519564.2	c.473C>G	p.Thr158Ser	missense_variant	5/5	2	NM_001178089.3	ENSP00000430354	P1
ZNF454	ENST00000320129.7	c.473C>G	p.Thr158Ser	missense_variant	5/5	2		ENSP00000326249	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

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

Apr 08, 2024

The c.473C>G (p.T158S) alteration is located in exon 5 (coding exon 4) of the ZNF454 gene. This alteration results from a C to G substitution at nucleotide position 473, causing the threonine (T) at amino acid position 158 to be replaced by a serine (S). 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	0.067
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.16
DANN	Benign	0.41
DEOGEN2	Benign	0.00051	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.050	.;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.056
Sift	Benign	0.90	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.041	B;B
Vest4		0.098
MutPred		0.23		Loss of glycosylation at T158 (P = 0.0096);Loss of glycosylation at T158 (P = 0.0096);
MVP		0.19
MPC		0.27
ClinPred		0.11	T
GERP RS		-0.15
Varity_R		0.064
gMVP		0.043

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: chr5-178391878;