12-133188055-A-G

Variant names:

• chr12-133188055-A-G
• NM_003415.3:c.217A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003415.3(ZNF268):​c.217A>G​(p.Lys73Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,437,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ZNF268 NM_003415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.63
• Publications: 0 publications found

Genes affected

ZNF268 (HGNC:13061): (zinc finger protein 268) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in several processes, including positive regulation of NIK/NF-kappaB signaling; positive regulation of nitrogen compound metabolic process; and regulation of apoptotic process. Located in actin cytoskeleton; cytosol; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000256825 (HGNC:):

ACMG classification

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=0.08042961).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003415.3. 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
	ZNF268	NM_003415.3	MANE Select	c.217A>G	p.Lys73Glu	missense	Exon 3 of 6	NP_003406.1	Q14587-1
	ZNF268	NM_001165881.3		c.217A>G	p.Lys73Glu	missense	Exon 3 of 6	NP_001159353.1	Q14587-1
	ZNF268	NM_152943.3		c.217A>G	p.Lys73Glu	missense	Exon 3 of 7	NP_694422.2	A0A075B6T9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF268	ENST00000536435.7	TSL:1 MANE Select	c.217A>G	p.Lys73Glu	missense	Exon 3 of 6	ENSP00000444412.3	Q14587-1
	ZNF268	ENST00000228289.9	TSL:1	c.217A>G	p.Lys73Glu	missense	Exon 3 of 6	ENSP00000228289.5	Q14587-1
	ENSG00000256825	ENST00000540096.2	TSL:2	c.712A>G	p.Lys238Glu	missense	Exon 7 of 11	ENSP00000457704.2	A0A088AWK7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1437984 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712896

African (AFR) AF: 0.0000302 AC: 1 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 41402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25580

East Asian (EAS) AF: 0.00 AC: 0 AN: 39158

South Asian (SAS) AF: 0.00 AC: 0 AN: 82550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5092

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099854

Other (OTH) AF: 0.00 AC: 0 AN: 59524

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	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.057
DANN	Benign	0.51
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.20	N
PhyloP100		-1.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.011
Sift	Benign	0.34	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.075
MutPred		0.47		Loss of ubiquitination at K73 (P = 0.0141)
MVP		0.040
MPC		0.11
ClinPred		0.038	T
GERP RS		-4.1
Varity_R		0.055
gMVP		0.019
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: chr12-133764641;