19-58470891-G-T

Variant names:

• chr19-58470891-G-T
• rs1323670824
• NM_014347.3:c.399G>T

Variant summary

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

The NM_014347.3(ZNF324):​c.399G>T​(p.Glu133Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZNF324 NM_014347.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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=0.17599696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF324	NM_014347.3	c.399G>T	p.Glu133Asp	missense_variant	Exon 4 of 4	ENST00000196482.4	NP_055162.1
ZNF324	XM_005258713.5	c.414G>T	p.Glu138Asp	missense_variant	Exon 4 of 4		XP_005258770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF324	ENST00000196482.4	c.399G>T	p.Glu133Asp	missense_variant	Exon 4 of 4	1	NM_014347.3	ENSP00000196482.3
ZNF324	ENST00000536459.6	c.399G>T	p.Glu133Asp	missense_variant	Exon 4 of 4	2		ENSP00000444812.1
ZNF324	ENST00000593925.1	c.-28G>T		upstream_gene_variant		2		ENSP00000471778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

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.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.399G>T (p.E133D) alteration is located in exon 4 (coding exon 3) of the ZNF324 gene. This alteration results from a G to T substitution at nucleotide position 399, causing the glutamic acid (E) at amino acid position 133 to be replaced by an aspartic acid (D). 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	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	.;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	T;.;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	.;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	.;N;N
REVEL	Benign	0.047
Sift	Benign	0.16	.;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.74	.;P;P
Vest4		0.25
MutPred		0.20		Loss of methylation at K135 (P = 0.1103);Loss of methylation at K135 (P = 0.1103);Loss of methylation at K135 (P = 0.1103);
MVP		0.28
MPC		1.2
ClinPred		0.69	D
GERP RS		3.4
Varity_R		0.13
gMVP		0.067

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: rs1323670824; hg19: chr19-58982258;