5-178712112-T-A

Variant names:

• chr5-178712112-T-A
• rs781769046
• NM_005649.3:c.1766A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005649.3(ZNF354A):​c.1766A>T​(p.His589Leu) 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. 13/22 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: ZNF354A NM_005649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.360

Genes affected

ZNF354A (HGNC:11628): (zinc finger protein 354A) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in cytosol; nucleolus; and nucleoplasm. Biomarker of in situ carcinoma and seminoma. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285978 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11195475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF354A	NM_005649.3	c.1766A>T	p.His589Leu	missense_variant	Exon 5 of 5	ENST00000335815.7	NP_005640.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF354A	ENST00000335815.7	c.1766A>T	p.His589Leu	missense_variant	Exon 5 of 5	1	NM_005649.3	ENSP00000337122.2
ENSG00000285978	ENST00000638723.1	n.257-4940A>T		intron_variant	Intron 3 of 7	5		ENSP00000492050.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1766A>T (p.H589L) alteration is located in exon 5 (coding exon 4) of the ZNF354A gene. This alteration results from a A to T substitution at nucleotide position 1766, causing the histidine (H) at amino acid position 589 to be replaced by a leucine (L). 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	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.056	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N
PhyloP100		-0.36
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.078
Sift	Benign	0.11	T
Sift4G	Benign	0.56	T
Polyphen		0.33	B
Vest4		0.15
MutPred		0.50		Loss of disorder (P = 0.0506);
MVP		0.21
MPC		0.33
ClinPred		0.18	T
GERP RS		3.3
Varity_R		0.23
gMVP		0.16
Mutation Taster		=87/13	polymorphism

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

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Other links and lift over

dbSNP: rs781769046; hg19: chr5-178139113;