chr12-133202465-A-G

Variant names:

• chr12-133202465-A-G
• rs1014058483
• NM_003415.3:c.779A>G

Variant summary

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

The NM_003415.3(ZNF268):​c.779A>G​(p.Lys260Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,611,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: ZNF268 NM_003415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.244
• 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: 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=0.048718005).

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.779A>G	p.Lys260Arg	missense	Exon 6 of 6	NP_003406.1	Q14587-1
	ZNF268	NM_001165881.3		c.779A>G	p.Lys260Arg	missense	Exon 6 of 6	NP_001159353.1	Q14587-1
	ZNF268	NM_001165882.3		c.530A>G	p.Lys177Arg	missense	Exon 6 of 6	NP_001159354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF268	ENST00000536435.7	TSL:1 MANE Select	c.779A>G	p.Lys260Arg	missense	Exon 6 of 6	ENSP00000444412.3	Q14587-1
	ZNF268	ENST00000228289.9	TSL:1	c.779A>G	p.Lys260Arg	missense	Exon 6 of 6	ENSP00000228289.5	Q14587-1
	ZNF268	ENST00000541009.6	TSL:1	c.*303A>G		3_prime_UTR	Exon 7 of 7	ENSP00000439539.2	A0A075B6T9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000163 AC: 4 AN: 245534 AF XY: 0.0000150

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: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000685 AC: 100 AN: 1459716 Hom.: 0 Cov.: 34 AF XY: 0.0000620 AC XY: 45 AN XY: 725996

African (AFR) AF: 0.0000299 AC: 1 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000864 AC: 96 AN: 1110902

Other (OTH) AF: 0.0000498 AC: 3 AN: 60294

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions as Germline

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	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.53
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.24
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.019
Sift	Benign	0.63	T
Sift4G	Benign	0.96	T
Polyphen		0.0	B
Vest4		0.060
MutPred		0.36		Loss of ubiquitination at K260 (P = 0.0283)
MVP		0.10
MPC		0.022
ClinPred		0.035	T
GERP RS		-3.1
Varity_R		0.053
gMVP		0.014
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

dbSNP: rs1014058483; hg19: chr12-133779051;