10-122993968-G-T

Position:

• chr10-122993968-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001372123.1(IKZF5):​c.1072C>A​(p.Gln358Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKZF5 NM_001372123.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86

Genes affected

IKZF5 (HGNC:14283): (IKAROS family zinc finger 5) Members of the Ikaros (ZNFN1A1; MIM 603023) family of transcription factors, which includes Pegasus, are expressed in lymphocytes and are implicated in the control of lymphoid development.[supplied by OMIM, Jul 2002]

PSTK (HGNC:28578): (phosphoseryl-tRNA kinase) Predicted to enable kinase activity and tRNA binding activity. Predicted to be involved in phosphorylation; selenocysteinyl-tRNA(Sec) biosynthetic process; and translation. Predicted to act upstream of or within selenocysteine incorporation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IKZF5. . Gene score misZ 1.8899 (greater than the threshold 3.09). Trascript score misZ 3.2196 (greater than threshold 3.09). GenCC has associacion of gene with thrombocytopenia 7, autosomal thrombocytopenia with normal platelets.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4092689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF5	NM_001372123.1	c.1072C>A	p.Gln358Lys	missense_variant	5/5	ENST00000368886.10	NP_001359052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKZF5	ENST00000368886.10	c.1072C>A	p.Gln358Lys	missense_variant	5/5	1	NM_001372123.1	ENSP00000357881	P1
IKZF5	ENST00000617859.4	c.1072C>A	p.Gln358Lys	missense_variant	5/5	1		ENSP00000478056	P1
PSTK	ENST00000496079.1	n.586-675G>T		intron_variant, non_coding_transcript_variant		3
PSTK	ENST00000497219.5	n.1816-3151G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombocytopenia 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.013	T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.14	N;.
REVEL	Benign	0.28
Sift	Benign	0.62	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.28	B;B
Vest4		0.59
MutPred		0.56		Gain of methylation at Q358 (P = 0.0038);Gain of methylation at Q358 (P = 0.0038);
MVP		0.15
MPC		0.91
ClinPred		0.73	D
GERP RS		6.0
Varity_R		0.16
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-124753484;