6-28365591-C-G

Variant names:

• chr6-28365591-C-G
• NM_024493.4:c.923C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024493.4(ZKSCAN3):​c.923C>G​(p.Ala308Gly) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZKSCAN3 NM_024493.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.336
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060426116).

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.923C>G	p.Ala308Gly	missense	Exon 6 of 6	NP_077819.2	Q9BRR0-1
	ZKSCAN3	NM_001242894.2		c.923C>G	p.Ala308Gly	missense	Exon 7 of 7	NP_001229823.1	Q9BRR0-1
	ZKSCAN3	NM_001242895.2		c.479C>G	p.Ala160Gly	missense	Exon 5 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.923C>G	p.Ala308Gly	missense	Exon 6 of 6	ENSP00000252211.2	Q9BRR0-1
	ZKSCAN3	ENST00000377255.3	TSL:1	c.923C>G	p.Ala308Gly	missense	Exon 7 of 7	ENSP00000366465.1	Q9BRR0-1
	ZKSCAN3	ENST00000881832.1		c.923C>G	p.Ala308Gly	missense	Exon 6 of 6	ENSP00000551891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	0.098
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.8
DANN	Benign	0.88
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.0058	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.34
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.082
Sift	Benign	0.30	T
Sift4G	Benign	0.34	T
Polyphen		0.92	P
Vest4		0.086
MutPred		0.34		Gain of catalytic residue at A308 (P = 0.0763)
MVP		0.061
MPC		0.23
ClinPred		0.12	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.027
Mutation Taster		=98/2	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

hg19: chr6-28333368;