18-35337606-G-T

Variant names:

• chr18-35337606-G-T
• NM_006965.4:c.733C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006965.4(ZNF24):​c.733C>A​(p.Pro245Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P245S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF24 NM_006965.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27441266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF24	NM_006965.4	c.733C>A	p.Pro245Thr	missense_variant	Exon 4 of 4	ENST00000261332.11	NP_008896.2
ZNF24	NM_001375815.1	c.733C>A	p.Pro245Thr	missense_variant	Exon 4 of 4		NP_001362744.1
ZNF24	NM_001308123.2	c.*1454C>A		3_prime_UTR_variant	Exon 4 of 4		NP_001295052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF24	ENST00000261332.11	c.733C>A	p.Pro245Thr	missense_variant	Exon 4 of 4	1	NM_006965.4	ENSP00000261332.5
ZNF24	ENST00000399061.3	c.733C>A	p.Pro245Thr	missense_variant	Exon 4 of 4	1		ENSP00000382015.2
ZNF24	ENST00000589881	c.*1454C>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000467655.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733C>A (p.P245T) alteration is located in exon 4 (coding exon 3) of the ZNF24 gene. This alteration results from a C to A substitution at nucleotide position 733, causing the proline (P) at amino acid position 245 to be replaced by a threonine (T). 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	0.090
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.027	.;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.15
Sift	Benign	0.12	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.96	D;D
Vest4		0.45
MutPred		0.34		Gain of phosphorylation at P245 (P = 0.0181);Gain of phosphorylation at P245 (P = 0.0181);
MVP		0.12
MPC		1.1
ClinPred		0.85	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.51

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: chr18-32917570;