chr12-133202503-G-A

Variant names:

• chr12-133202503-G-A
• rs373015628
• NM_003415.3:c.817G>A

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.817G>A​(p.Glu273Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,612,120 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: ZNF268 NM_003415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• Publications: 3 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=0.010117233).

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.817G>A	p.Glu273Lys	missense	Exon 6 of 6	NP_003406.1	Q14587-1
	ZNF268	NM_001165881.3		c.817G>A	p.Glu273Lys	missense	Exon 6 of 6	NP_001159353.1	Q14587-1
	ZNF268	NM_001165882.3		c.568G>A	p.Glu190Lys	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.817G>A	p.Glu273Lys	missense	Exon 6 of 6	ENSP00000444412.3	Q14587-1
	ZNF268	ENST00000228289.9	TSL:1	c.817G>A	p.Glu273Lys	missense	Exon 6 of 6	ENSP00000228289.5	Q14587-1
	ZNF268	ENST00000541009.6	TSL:1	c.*341G>A		3_prime_UTR	Exon 7 of 7	ENSP00000439539.2	A0A075B6T9

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152052 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000179 AC: 44 AN: 246102 AF XY: 0.000142

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.00362

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1459950 Hom.: 1 Cov.: 34 AF XY: 0.0000964 AC XY: 70 AN XY: 726156

African (AFR) AF: 0.0000598 AC: 2 AN: 33436

American (AMR) AF: 0.0000451 AC: 2 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 98 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111064

Other (OTH) AF: 0.000249 AC: 15 AN: 60296

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74410

African (AFR) AF: 0.0000481 AC: 2 AN: 41544

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67958

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000383 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000132 AC: 16

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	0.066
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.092
Sift	Benign	0.056	T
Sift4G	Benign	0.080	T
Polyphen		0.0070	B
Vest4		0.22
MVP		0.18
MPC		0.039
ClinPred		0.024	T
GERP RS		1.0
Varity_R		0.047
gMVP		0.022
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: rs373015628; hg19: chr12-133779089; COSMIC: COSV57214154; COSMIC: COSV57214154;