rs775444456

Variant names:

• chr12-133191505-T-C
• rs775444456
• NM_003415.3:c.251T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PVS1_Supporting

The NM_001165882.3(ZNF268):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ZNF268 NM_001165882.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.393
• 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 1 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 27 codons. Genomic position: 133191582. Lost 0.030 part of the original CDS.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165882.3. 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.251T>C	p.Met84Thr	missense	Exon 4 of 6	NP_003406.1	Q14587-1
	ZNF268	NM_001165882.3		c.2T>C	p.Met1?	start_lost	Exon 4 of 6	NP_001159354.1
	ZNF268	NM_001165881.3		c.251T>C	p.Met84Thr	missense	Exon 4 of 6	NP_001159353.1	Q14587-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF268	ENST00000536435.7	TSL:1 MANE Select	c.251T>C	p.Met84Thr	missense	Exon 4 of 6	ENSP00000444412.3	Q14587-1
	ZNF268	ENST00000228289.9	TSL:1	c.251T>C	p.Met84Thr	missense	Exon 4 of 6	ENSP00000228289.5	Q14587-1
	ENSG00000256825	ENST00000540096.2	TSL:2	c.746T>C	p.Met249Thr	missense	Exon 8 of 11	ENSP00000457704.2	A0A088AWK7

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000361 AC: 9 AN: 249396 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111918

Other (OTH) AF: 0.0000828 AC: 5 AN: 60370

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74444

African (AFR) AF: 0.0000481 AC: 2 AN: 41550

American (AMR) AF: 0.000589 AC: 9 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.00

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	0.086
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.1
DANN	Benign	0.79
DEOGEN2	Benign	0.00019	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.59	N
PhyloP100		-0.39
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.25
Sift	Benign	0.17	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.47		Loss of stability (P = 0.0021)
MVP		0.13
MPC		0.12
ClinPred		0.027	T
GERP RS		-1.0
PromoterAI		0.023	Neutral
Varity_R		0.098
gMVP		0.031
Mutation Taster		=99/1	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: rs775444456; hg19: chr12-133768091;