6-28153643-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006298.4(ZKSCAN8):c.1363A>G(p.Ile455Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZKSCAN8 NM_006298.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

Genes affected

ZKSCAN8 (HGNC:12983): (zinc finger with KRAB and SCAN domains 8) 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13776144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZKSCAN8	NM_006298.4	c.1363A>G	p.Ile455Val	missense_variant	6/6	ENST00000330236.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZKSCAN8	ENST00000330236.7	c.1363A>G	p.Ile455Val	missense_variant	6/6	1	NM_006298.4	P1
ZKSCAN8	ENST00000457389.6	c.1363A>G	p.Ile455Val	missense_variant	7/7	1		P1
ZKSCAN8	ENST00000606198.5	c.*900A>G		3_prime_UTR_variant, NMD_transcript_variant	6/6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The c.1363A>G (p.I455V) alteration is located in exon 6 (coding exon 5) of the ZKSCAN8 gene. This alteration results from a A to G substitution at nucleotide position 1363, causing the isoleucine (I) at amino acid position 455 to be replaced by a valine (V). 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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0043	T;T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.031	N
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.50	N;N
MutationTaster	Benign	0.84	N;N
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.63	N;N
REVEL	Benign	0.21
Sift	Benign	0.034	D;D
Sift4G	Benign	0.090	T;T
Polyphen		0.56	P;P
Vest4		0.18
MutPred		0.35		Loss of ubiquitination at K460 (P = 0.1037);Loss of ubiquitination at K460 (P = 0.1037);
MVP		0.28
MPC		0.51
ClinPred		0.38	T
GERP RS		6.0
Varity_R		0.060
gMVP		0.072

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-28121421;