rs766690331

Variant names:

• chr12-133202597-A-G
• rs766690331
• NM_003415.3:c.911A>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.911A>G​(p.Tyr304Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000772 in 1,606,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: ZNF268 NM_003415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.686
• 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=0.092930526).

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.911A>G	p.Tyr304Cys	missense	Exon 6 of 6	NP_003406.1	Q14587-1
	ZNF268	NM_001165881.3		c.911A>G	p.Tyr304Cys	missense	Exon 6 of 6	NP_001159353.1	Q14587-1
	ZNF268	NM_001165882.3		c.662A>G	p.Tyr221Cys	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.911A>G	p.Tyr304Cys	missense	Exon 6 of 6	ENSP00000444412.3	Q14587-1
	ZNF268	ENST00000228289.9	TSL:1	c.911A>G	p.Tyr304Cys	missense	Exon 6 of 6	ENSP00000228289.5	Q14587-1
	ZNF268	ENST00000541009.6	TSL:1	c.*435A>G		3_prime_UTR	Exon 7 of 7	ENSP00000439539.2	A0A075B6T9

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000808 AC: 19 AN: 235076 AF XY: 0.000110

Gnomad AFR exome AF: 0.0000698

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000825 AC: 120 AN: 1453910 Hom.: 0 Cov.: 34 AF XY: 0.0000858 AC XY: 62 AN XY: 722566

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.0000464 AC: 2 AN: 43120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25868

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39524

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000957 AC: 106 AN: 1107804

Other (OTH) AF: 0.0000166 AC: 1 AN: 60112

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

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: 5202

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

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

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000990 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.087
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.69
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.090
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0010	B
Vest4		0.26
MVP		0.18
MPC		0.13
ClinPred		0.086	T
GERP RS		0.35
Varity_R		0.15
gMVP		0.059
Mutation Taster		=91/9	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: rs766690331; hg19: chr12-133779183;