chr12-133202210-C-T

Variant names:

• chr12-133202210-C-T
• rs7975069
• NM_003415.3:c.524C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003415.3(ZNF268):​c.524C>T​(p.Thr175Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,606,872 control chromosomes in the GnomAD database, including 92,427 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T175T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.34 (9410 hom., cov: 33)
  • Exomes 𝑓: 0.33 (83017 hom.)
• Consequence: ZNF268 NM_003415.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.828
• Publications: 36 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8822503E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF268	NM_003415.3	MANE Select	c.524C>T	p.Thr175Met	missense	Exon 6 of 6	NP_003406.1
	ZNF268	NM_001165881.3		c.524C>T	p.Thr175Met	missense	Exon 6 of 6	NP_001159353.1
	ZNF268	NM_001165882.3		c.275C>T	p.Thr92Met	missense	Exon 6 of 6	NP_001159354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF268	ENST00000536435.7	TSL:1 MANE Select	c.524C>T	p.Thr175Met	missense	Exon 6 of 6	ENSP00000444412.3
	ZNF268	ENST00000228289.9	TSL:1	c.524C>T	p.Thr175Met	missense	Exon 6 of 6	ENSP00000228289.5
	ZNF268	ENST00000541211.6	TSL:1	c.397C>T	p.Arg133Trp	missense	Exon 5 of 5	ENSP00000442446.2

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52171 AN: 151694 Hom.: 9402 Cov.: 33

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.0868

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.300

GnomAD2 exomes AF: 0.308 AC: 74980 AN: 243244 AF XY: 0.309

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.0733

Gnomad FIN exome AF: 0.322

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.333 AC: 484960 AN: 1455060 Hom.: 83017 Cov.: 37 AF XY: 0.333 AC XY: 240496 AN XY: 723214

African (AFR) AF: 0.422 AC: 14032 AN: 33238

American (AMR) AF: 0.255 AC: 11120 AN: 43620

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8642 AN: 25866

East Asian (EAS) AF: 0.0779 AC: 3087 AN: 39604

South Asian (SAS) AF: 0.292 AC: 24850 AN: 84978

European-Finnish (FIN) AF: 0.320 AC: 17004 AN: 53176

Middle Eastern (MID) AF: 0.289 AC: 1661 AN: 5738

European-Non Finnish (NFE) AF: 0.347 AC: 385240 AN: 1108708

Other (OTH) AF: 0.321 AC: 19324 AN: 60132

GnomAD4 genome AF: 0.344 AC: 52210 AN: 151812 Hom.: 9410 Cov.: 33 AF XY: 0.338 AC XY: 25108 AN XY: 74194

African (AFR) AF: 0.414 AC: 17146 AN: 41412

American (AMR) AF: 0.278 AC: 4238 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1131 AN: 3468

East Asian (EAS) AF: 0.0872 AC: 450 AN: 5160

South Asian (SAS) AF: 0.280 AC: 1344 AN: 4808

European-Finnish (FIN) AF: 0.327 AC: 3442 AN: 10514

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23487 AN: 67906

Other (OTH) AF: 0.300 AC: 633 AN: 2112

Alfa AF: 0.338 Hom.: 19154

Bravo AF: 0.341

TwinsUK AF: 0.355 AC: 1318

ALSPAC AF: 0.346 AC: 1335

ESP6500AA AF: 0.408 AC: 1522

ESP6500EA AF: 0.331 AC: 2710

ExAC AF: 0.314 AC: 37879

Asia WGS AF: 0.206 AC: 718 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.31
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.00069	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.83
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.011
Sift	Benign	0.099	T
Sift4G	Uncertain	0.010	D
Vest4		0.12
ClinPred		0.00098	T
GERP RS		-0.17
Varity_R		0.0070
Mutation Taster		=99/1	polymorphism (auto)

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: rs7975069; hg19: chr12-133778796; COSMIC: COSV107195902; COSMIC: COSV107195902;