18-35337606-G-A

Variant names:

• chr18-35337606-G-A
• rs142376346
• NM_006965.4:c.733C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006965.4(ZNF24):​c.733C>T​(p.Pro245Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000638 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. P245T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037519693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF24	NM_006965.4	c.733C>T	p.Pro245Ser	missense_variant	Exon 4 of 4	ENST00000261332.11	NP_008896.2
ZNF24	NM_001375815.1	c.733C>T	p.Pro245Ser	missense_variant	Exon 4 of 4		NP_001362744.1
ZNF24	NM_001308123.2	c.*1454C>T		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>T	p.Pro245Ser	missense_variant	Exon 4 of 4	1	NM_006965.4	ENSP00000261332.5
ZNF24	ENST00000399061.3	c.733C>T	p.Pro245Ser	missense_variant	Exon 4 of 4	1		ENSP00000382015.2
ZNF24	ENST00000589881	c.*1454C>T		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000467655.1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000462 AC: 116 AN: 251138 Hom.: 0 AF XY: 0.000508 AC XY: 69 AN XY: 135732

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000714

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000653 AC: 954 AN: 1461786 Hom.: 0 Cov.: 36 AF XY: 0.000664 AC XY: 483 AN XY: 727198

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000788

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74464

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000698 Hom.: 0

Bravo AF: 0.000506

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733C>T (p.P245S) alteration is located in exon 4 (coding exon 3) of the ZNF24 gene. This alteration results from a C to T substitution at nucleotide position 733, causing the proline (P) at amino acid position 245 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	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.013	.;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.13
Sift	Benign	0.43	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.96	D;D
Vest4		0.36
MVP		0.15
MPC		1.0
ClinPred		0.047	T
GERP RS		5.3
Varity_R		0.10
gMVP		0.50

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: rs142376346; hg19: chr18-32917570; COSMIC: COSV54348551; COSMIC: COSV54348551;