Genetic Variant NM_024493.4:c.995A>G (chr6-28365663-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024493.4(ZKSCAN3):c.995A>G(p.His332Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ZKSCAN3
NM_024493.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.78

Publications

0 publications found

Variant links:

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]

ZKSCAN3 links:

ENSG00000294493 (HGNC:):

ENSG00000294493 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZKSCAN3	NM_024493.4	MANE Select	c.995A>G	p.His332Arg	missense	Exon 6 of 6	NP_077819.2	Q9BRR0-1
ZKSCAN3	NM_001242894.2		c.995A>G	p.His332Arg	missense	Exon 7 of 7	NP_001229823.1	Q9BRR0-1
ZKSCAN3	NM_001242895.2		c.551A>G	p.His184Arg	missense	Exon 5 of 5	NP_001229824.1	Q9BRR0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZKSCAN3	ENST00000252211.7	TSL:1 MANE Select	c.995A>G	p.His332Arg	missense	Exon 6 of 6	ENSP00000252211.2	Q9BRR0-1
ZKSCAN3	ENST00000377255.3	TSL:1	c.995A>G	p.His332Arg	missense	Exon 7 of 7	ENSP00000366465.1	Q9BRR0-1
ZKSCAN3	ENST00000881832.1		c.995A>G	p.His332Arg	missense	Exon 6 of 6	ENSP00000551891.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251426

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.80

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

4.1

PhyloP100

8.8

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.3

REVEL

Uncertain

0.64

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.67

MVP

0.90

MPC

0.74

ClinPred

0.99

GERP RS

3.7

Varity_R

0.56

gMVP

0.32

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over