Genetic Variant ZKSCAN7:p.Arg223Trp (chr3-44567986-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001288590.2(ZKSCAN7):c.667C>T(p.Arg223Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 1,299,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ZKSCAN7
NM_001288590.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.660

Publications

1 publications found

Variant links:

Genes affected

ZKSCAN7 (HGNC:12955): (zinc finger with KRAB and SCAN domains 7) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZKSCAN7 links:

ZKSCAN7-AS1 (HGNC:53964): (ZKSCAN7 ZNF cluster antisense RNA 1)

ZKSCAN7-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.101014555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZKSCAN7	NM_001288590.2 link	c.667C>T	p.Arg223Trp	missense_variant	Exon 4 of 6	ENST00000426540.6	NP_001275519.1	Q9P0L1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZKSCAN7	ENST00000426540.6 link	c.667C>T	p.Arg223Trp	missense_variant	Exon 4 of 6	2	NM_001288590.2	ENSP00000395524.1		Q9P0L1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000757

AC:

AN:

132122

AF XY:

0.00

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.0000197

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000177

AC:

AN:

1299436

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

641528

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29398

American (AMR)

AF:

0.00

AC:

AN:

33884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23102

East Asian (EAS)

AF:

0.00

AC:

AN:

35078

South Asian (SAS)

AF:

0.0000134

AC:

AN:

74590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4024

European-Non Finnish (NFE)

AF:

0.0000201

AC:

AN:

996540

Other (OTH)

AF:

0.0000368

AC:

AN:

54314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 30, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.667C>T (p.R223W) alteration is located in exon 4 (coding exon 3) of the ZKSCAN7 gene. This alteration results from a C to T substitution at nucleotide position 667, causing the arginine (R) at amino acid position 223 to be replaced by a tryptophan (W). 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

0.13

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;.;T;T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.038

M_CAP

Benign

0.012

MetaRNN

Benign

0.10

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M;M;M;.;.

PhyloP100

0.66

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Benign

0.092

Sift

Benign

0.068

T;D;D;T;D;D

Sift4G

Benign

0.093

T;D;D;T;T;D

Polyphen

0.98

D;D;D;D;.;.

Vest4

0.17

MutPred

0.38

Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);.;.;

MVP

0.31

MPC

0.25

ClinPred

0.64

GERP RS

0.62

Varity_R

0.052

gMVP

0.063

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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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3-44567986-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over