rs115751349

chr5-157232393-C-Gchr5-157232393-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005546.4(ITK):c.767C>G(p.Thr256Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T256I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ITK NM_005546.4 missense, splice_region
• Scores: Splicing: ADA: 0.9685
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20

Genes affected

ITK (HGNC:6171): (IL2 inducible T cell kinase) This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein contains both SH2 and SH3 domains which are often found in intracellular kinases. It is thought to play a role in T-cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITK	NM_005546.4	c.767C>G	p.Thr256Arg	missense_variant, splice_region_variant	8/17	ENST00000422843.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITK	ENST00000422843.8	c.767C>G	p.Thr256Arg	missense_variant, splice_region_variant	8/17	1	NM_005546.4	P1
ITK	ENST00000519402.5	n.902C>G		splice_region_variant, non_coding_transcript_exon_variant	8/16	2
ITK	ENST00000519759.1	n.386C>G		splice_region_variant, non_coding_transcript_exon_variant	3/5	4
ITK	ENST00000696962.1	c.767C>G	p.Thr256Arg	missense_variant, splice_region_variant, NMD_transcript_variant	8/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444742 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 719804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.080
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.040	N
MutationTaster	Benign	0.92	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.014	D
Sift4G	Benign	0.097	T
Polyphen		0.096	B
Vest4		0.45
MutPred		0.49		Gain of MoRF binding (P = 0.0404);
MVP		0.96
MPC		0.49
ClinPred		0.58	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.84
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

LitVar

Other links and lift over

dbSNP: rs115751349; hg19: chr5-156659403;