rs733743

Positions:

• chr6-28359594-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024493.4(ZKSCAN3):​c.8G>C​(p.Arg3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 1,613,460 control chromosomes in the GnomAD database, including 5,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.077 (551 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4998 hom.)
• Consequence: ZKSCAN3 NM_024493.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423

Genes affected

ZKSCAN3 (HGNC:13853): (zinc finger with KRAB and SCAN domains 3) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and chromatin binding activity. Involved in several processes, including negative regulation of autophagy; negative regulation of cellular senescence; and regulation of transcription, DNA-templated. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015053153).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZKSCAN3	NM_024493.4	c.8G>C	p.Arg3Thr	missense_variant	2/6	ENST00000252211.7	NP_077819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZKSCAN3	ENST00000252211.7	c.8G>C	p.Arg3Thr	missense_variant	2/6	1	NM_024493.4	ENSP00000252211.2
ZKSCAN3	ENST00000377255.3	c.8G>C	p.Arg3Thr	missense_variant	3/7	1		ENSP00000366465.1
ZKSCAN3	ENST00000341464.9	c.-42-1730G>C		intron_variant		2		ENSP00000341883.5

Frequencies

GnomAD3 genomes AF: 0.0771 AC: 11739 AN: 152168 Hom.: 551 Cov.: 32

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0962

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.0611

Gnomad FIN AF: 0.0945

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.0659

GnomAD3 exomes AF: 0.0880 AC: 22112 AN: 251228 Hom.: 1425 AF XY: 0.0839 AC XY: 11387 AN XY: 135794

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0323

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.0461

Gnomad FIN exome AF: 0.0983

Gnomad NFE exome AF: 0.0737

Gnomad OTH exome AF: 0.0669

GnomAD4 exome AF: 0.0763 AC: 111457 AN: 1461174 Hom.: 4998 Cov.: 31 AF XY: 0.0751 AC XY: 54616 AN XY: 726760

Gnomad4 AFR exome AF: 0.0588

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.0331

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.0487

Gnomad4 FIN exome AF: 0.0945

Gnomad4 NFE exome AF: 0.0734

Gnomad4 OTH exome AF: 0.0694

GnomAD4 genome AF: 0.0771 AC: 11738 AN: 152286 Hom.: 551 Cov.: 32 AF XY: 0.0788 AC XY: 5863 AN XY: 74448

Gnomad4 AFR AF: 0.0612

Gnomad4 AMR AF: 0.0962

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.0612

Gnomad4 FIN AF: 0.0945

Gnomad4 NFE AF: 0.0713

Gnomad4 OTH AF: 0.0652

Alfa AF: 0.0674 Hom.: 123

Bravo AF: 0.0802

TwinsUK AF: 0.0728 AC: 270

ALSPAC AF: 0.0734 AC: 283

ESP6500AA AF: 0.0601 AC: 265

ESP6500EA AF: 0.0703 AC: 605

ExAC AF: 0.0854 AC: 10375

Asia WGS AF: 0.0880 AC: 306 AN: 3478

EpiCase AF: 0.0609

EpiControl AF: 0.0668

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.0026	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.32	T;.
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.050
Sift	Benign	0.50	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.80	P;P
Vest4		0.38
MPC		2.1
ClinPred		0.0076	T
GERP RS		2.9
Varity_R		0.051
gMVP		0.66

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: rs733743; hg19: chr6-28327371; COSMIC: COSV52853798; COSMIC: COSV52853798;