18-35340576-T-A

Variant names:

• chr18-35340576-T-A
• rs1388694123
• NM_006965.4:c.75A>T

Variant summary

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

The NM_006965.4(ZNF24):​c.75A>T​(p.Arg25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: ZNF24 NM_006965.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.716

Genes affected

ZNF24 (HGNC:13032): (zinc finger protein 24) Enables DNA-binding transcription activator activity, RNA polymerase II-specific; identical protein binding activity; and sequence-specific DNA binding activity. Involved in negative regulation of transcription, DNA-templated and positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. [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=0.09008473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF24	NM_006965.4	c.75A>T	p.Arg25Ser	missense_variant	Exon 2 of 4	ENST00000261332.11	NP_008896.2
ZNF24	NM_001375815.1	c.75A>T	p.Arg25Ser	missense_variant	Exon 2 of 4		NP_001362744.1
ZNF24	NM_001308123.2	c.75A>T	p.Arg25Ser	missense_variant	Exon 2 of 4		NP_001295052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF24	ENST00000261332.11	c.75A>T	p.Arg25Ser	missense_variant	Exon 2 of 4	1	NM_006965.4	ENSP00000261332.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.75A>T (p.R25S) alteration is located in exon 2 (coding exon 1) of the ZNF24 gene. This alteration results from a A to T substitution at nucleotide position 75, causing the arginine (R) at amino acid position 25 to be replaced by a serine (S). 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	0.40
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.082	T;.;T;T;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.70	.;T;T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.090	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;L;L;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.080	N;.;N;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.73	T;.;T;.;.;.
Sift4G	Benign	0.63	T;T;T;.;T;T
Polyphen		0.056	B;B;B;.;.;.
Vest4		0.54
MutPred		0.33		Gain of phosphorylation at R25 (P = 0.0162);Gain of phosphorylation at R25 (P = 0.0162);Gain of phosphorylation at R25 (P = 0.0162);Gain of phosphorylation at R25 (P = 0.0162);Gain of phosphorylation at R25 (P = 0.0162);Gain of phosphorylation at R25 (P = 0.0162);
MVP		0.42
MPC		0.71
ClinPred		0.24	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.58

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: rs1388694123; hg19: chr18-32920540;