6-28365722-A-C

Position:

• chr6-28365722-A-C

Variant summary

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

The NM_024493.4(ZKSCAN3):​c.1054A>C​(p.Ile352Leu) 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: 33)
• Consequence: ZKSCAN3 NM_024493.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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 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=0.20779768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZKSCAN3	NM_024493.4	c.1054A>C	p.Ile352Leu	missense_variant	6/6	ENST00000252211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZKSCAN3	ENST00000252211.7	c.1054A>C	p.Ile352Leu	missense_variant	6/6	1	NM_024493.4	P1
ZKSCAN3	ENST00000377255.3	c.1054A>C	p.Ile352Leu	missense_variant	7/7	1		P1
ZKSCAN3	ENST00000341464.9	c.610A>C	p.Ile204Leu	missense_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 12, 2023

The c.1054A>C (p.I352L) alteration is located in exon 7 (coding exon 5) of the ZKSCAN3 gene. This alteration results from a A to C substitution at nucleotide position 1054, causing the isoleucine (I) at amino acid position 352 to be replaced by a leucine (L). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0028	T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.038	T;T;.
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.050	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.058	T;T;T
Sift4G	Benign	0.073	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.20
MutPred		0.44		Loss of catalytic residue at L357 (P = 0.0298);.;Loss of catalytic residue at L357 (P = 0.0298);
MVP		0.32
MPC		0.51
ClinPred		0.75	D
GERP RS		3.6
Varity_R		0.069
gMVP		0.015

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr6-28333499;