5-178712148-G-A

Position:

• chr5-178712148-G-A

Variant summary

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

The NM_005649.3(ZNF354A):​c.1730C>T​(p.Pro577Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZNF354A NM_005649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF354A	NM_005649.3	c.1730C>T	p.Pro577Leu	missense_variant	5/5	ENST00000335815.7	NP_005640.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF354A	ENST00000335815.7	c.1730C>T	p.Pro577Leu	missense_variant	5/5	1	NM_005649.3	ENSP00000337122.2
ENSG00000285978	ENST00000638723.1	n.257-4976C>T		intron_variant		5		ENSP00000492050.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727148

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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

Jul 19, 2023

The c.1730C>T (p.P577L) alteration is located in exon 5 (coding exon 4) of the ZNF354A gene. This alteration results from a C to T substitution at nucleotide position 1730, causing the proline (P) at amino acid position 577 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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0051	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Uncertain	0.31
Sift	Benign	0.075	T
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.58
MutPred		0.59		Loss of disorder (P = 0.0346);
MVP		0.48
MPC		0.81
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.42
gMVP		0.14

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: chr5-178139149;