chr6-28363723-C-T

Variant names:

• chr6-28363723-C-T
• rs373340452
• NM_024493.4:c.665C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024493.4(ZKSCAN3):​c.665C>T​(p.Thr222Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: ZKSCAN3 NM_024493.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.856
• Publications: 1 publications found

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]

ENSG00000294493 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05524385).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024493.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZKSCAN3	NM_024493.4	MANE Select	c.665C>T	p.Thr222Ile	missense	Exon 5 of 6	NP_077819.2	Q9BRR0-1
	ZKSCAN3	NM_001242894.2		c.665C>T	p.Thr222Ile	missense	Exon 6 of 7	NP_001229823.1	Q9BRR0-1
	ZKSCAN3	NM_001242895.2		c.221C>T	p.Thr74Ile	missense	Exon 4 of 5	NP_001229824.1	Q9BRR0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZKSCAN3	ENST00000252211.7	TSL:1 MANE Select	c.665C>T	p.Thr222Ile	missense	Exon 5 of 6	ENSP00000252211.2	Q9BRR0-1
	ZKSCAN3	ENST00000377255.3	TSL:1	c.665C>T	p.Thr222Ile	missense	Exon 6 of 7	ENSP00000366465.1	Q9BRR0-1
	ZKSCAN3	ENST00000881832.1		c.665C>T	p.Thr222Ile	missense	Exon 5 of 6	ENSP00000551891.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 251446 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000206 AC: 301 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.000213 AC XY: 155 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000246 AC: 273 AN: 1111940

Other (OTH) AF: 0.000149 AC: 9 AN: 60392

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.4
DANN	Benign	0.97
DEOGEN2	Benign	0.0061	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.86
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.011
Sift	Benign	0.10	T
Sift4G	Benign	0.47	T
Polyphen		0.21	B
Vest4		0.13
MVP		0.095
MPC		0.31
ClinPred		0.038	T
GERP RS		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.079
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs373340452; hg19: chr6-28331500;