12-56021521-C-T

Variant names:

• chr12-56021521-C-T
• rs778915947
• NM_022465.4:c.28C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001351092.2(IKZF4):​c.-185C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,608,146 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 0.000013 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: IKZF4 NM_001351092.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• Publications: 0 publications found

Genes affected

IKZF4 (HGNC:13179): (IKAROS family zinc finger 4) Members of the Ikaros (ZNFN1A1; MIM 603023) family of transcription factors, which includes Eos, are expressed in lymphocytes and are implicated in the control of lymphoid development.[supplied by OMIM, Jul 2002]

ENSG00000257449 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14278525).
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351092.2. 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
	IKZF4	NM_022465.4	MANE Select	c.28C>T	p.Arg10Cys	missense	Exon 1 of 8	NP_071910.3
	IKZF4	NM_001351092.2		c.-185C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001338021.1
	IKZF4	NM_001351089.2		c.28C>T	p.Arg10Cys	missense	Exon 5 of 12	NP_001338018.1	Q9H2S9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKZF4	ENST00000547167.6	TSL:1 MANE Select	c.28C>T	p.Arg10Cys	missense	Exon 1 of 8	ENSP00000448419.1	Q9H2S9-1
	IKZF4	ENST00000431367.6	TSL:1	c.28C>T	p.Arg10Cys	missense	Exon 2 of 9	ENSP00000412101.3	Q9H2S9-1
	IKZF4	ENST00000547791.2	TSL:1	c.46+71C>T		intron	N/A	ENSP00000450020.1	F8VPL6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151852 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

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: 0.0000127 AC: 3 AN: 236886 AF XY: 0.00000775

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000575

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1456294 Hom.: 0 Cov.: 38 AF XY: 0.0000138 AC XY: 10 AN XY: 723872

African (AFR) AF: 0.0000600 AC: 2 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39400

South Asian (SAS) AF: 0.00 AC: 0 AN: 85032

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52702

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1109888

Other (OTH) AF: 0.00 AC: 0 AN: 60108

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151852 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 74168

African (AFR) AF: 0.00 AC: 0 AN: 41290

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000827 AC: 1

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	0.20
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.10
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.35
MutPred		0.24		Loss of MoRF binding (P = 0.0094)
MVP		0.12
MPC		0.14
ClinPred		0.54	D
GERP RS		3.1
PromoterAI		-0.011	Neutral
Varity_R		0.10
gMVP		0.32
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs778915947; hg19: chr12-56415305;