18-35340370-A-T

Variant names:

• chr18-35340370-A-T
• NM_006965.4:c.281T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006965.4(ZNF24):​c.281T>A​(p.Leu94Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF24 NM_006965.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF24	NM_006965.4	c.281T>A	p.Leu94Gln	missense_variant	Exon 2 of 4	ENST00000261332.11	NP_008896.2
ZNF24	NM_001375815.1	c.281T>A	p.Leu94Gln	missense_variant	Exon 2 of 4		NP_001362744.1
ZNF24	NM_001308123.2	c.281T>A	p.Leu94Gln	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.281T>A	p.Leu94Gln	missense_variant	Exon 2 of 4	1	NM_006965.4	ENSP00000261332.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.281T>A (p.L94Q) alteration is located in exon 2 (coding exon 1) of the ZNF24 gene. This alteration results from a T to A substitution at nucleotide position 281, causing the leucine (L) at amino acid position 94 to be replaced by a glutamine (Q). 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	0.72
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;T;T;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	.;T;T;T;T;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.8	H;H;H;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	D;.;D;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;.;D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;D;D
Polyphen		0.99	D;D;D;.;.;.
Vest4		0.83
MutPred		0.89		Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);
MVP		0.33
MPC		1.3
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr18-32920334;