5-178965513-C-G

Position:

• chr5-178965513-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001178089.3(ZNF454):​c.1109C>G​(p.Ser370Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,848 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: 0.0000082 (0 hom.)
• Consequence: ZNF454 NM_001178089.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25878525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF454	NM_001178089.3	c.1109C>G	p.Ser370Cys	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.1109C>G	p.Ser370Cys	missense_variant	5/5	2	NM_001178089.3	ENSP00000430354	P1
ZNF454	ENST00000320129.7	c.1109C>G	p.Ser370Cys	missense_variant	5/5	2		ENSP00000326249	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461848 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

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

Nov 10, 2022

The c.1109C>G (p.S370C) 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 1109, causing the serine (S) at amino acid position 370 to be replaced by a cysteine (C). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.084
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.14	.;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.95	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.12
Sift	Benign	0.17	T;T
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;D
Vest4		0.30
MutPred		0.36		Gain of catalytic residue at L371 (P = 0.0121);Gain of catalytic residue at L371 (P = 0.0121);
MVP		0.32
MPC		0.99
ClinPred		0.89	D
GERP RS		3.5
Varity_R		0.19
gMVP		0.13

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: rs929797804; hg19: chr5-178392514;