10-122996024-G-A

Position:

• chr10-122996024-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_001372123.1(IKZF5):​c.286C>T​(p.Arg96Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKZF5 NM_001372123.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.39

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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775
• PP5: Variant 10-122996024-G-A is Pathogenic according to our data. Variant chr10-122996024-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1684458.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKZF5	NM_001372123.1	c.286C>T	p.Arg96Trp	missense_variant	4/5	ENST00000368886.10	NP_001359052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKZF5	ENST00000368886.10	c.286C>T	p.Arg96Trp	missense_variant	4/5	1	NM_001372123.1	ENSP00000357881	P1
IKZF5	ENST00000617859.4	c.286C>T	p.Arg96Trp	missense_variant	4/5	1		ENSP00000478056	P1
IKZF5	ENST00000496605.5	n.584C>T		non_coding_transcript_exon_variant	4/4	2
PSTK	ENST00000497219.5	n.1816-1095G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Thrombocytopenia 7 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 23, 2020	- -
Likely pathogenic, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.081	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;.
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.58		Gain of catalytic residue at A95 (P = 0.0471);Gain of catalytic residue at A95 (P = 0.0471);
MVP		0.38
MPC		1.6
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.13
gMVP		0.78

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: chr10-124755540;