19-58469775-G-A

Variant names:

• chr19-58469775-G-A
• rs758776004
• NM_014347.3:c.169G>A

Variant summary

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

The NM_014347.3(ZNF324):​c.169G>A​(p.Glu57Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,443,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ZNF324 NM_014347.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.610

Genes affected

ZNF324 (HGNC:14096): (zinc finger protein 324) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Acts upstream of or within with a positive effect on G1/S transition of mitotic cell cycle and cell population proliferation. 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=0.07242176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF324	NM_014347.3	c.169G>A	p.Glu57Lys	missense_variant	Exon 3 of 4	ENST00000196482.4	NP_055162.1
ZNF324	XM_005258713.5	c.184G>A	p.Glu62Lys	missense_variant	Exon 3 of 4		XP_005258770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF324	ENST00000196482.4	c.169G>A	p.Glu57Lys	missense_variant	Exon 3 of 4	1	NM_014347.3	ENSP00000196482.3
ZNF324	ENST00000536459.6	c.169G>A	p.Glu57Lys	missense_variant	Exon 3 of 4	2		ENSP00000444812.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000485 AC: 7 AN: 1443492 Hom.: 0 Cov.: 31 AF XY: 0.00000419 AC XY: 3 AN XY: 716220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.0000502

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169G>A (p.E57K) alteration is located in exon 3 (coding exon 2) of the ZNF324 gene. This alteration results from a G to A substitution at nucleotide position 169, causing the glutamic acid (E) at amino acid position 57 to be replaced by a lysine (K). 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	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	.;T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.33	T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.49	.;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	.;N;N
REVEL	Benign	0.019
Sift	Benign	0.13	.;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.10	.;B;B
Vest4		0.21
MVP		0.22
MPC		0.76
ClinPred		0.15	T
GERP RS		0.46
Varity_R		0.10
gMVP		0.11

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: rs758776004; hg19: chr19-58981142;