NM_005546.4:c.138+3367T>C

Variant names:

• chr5-157184482-T-C
• rs452223
• NM_005546.4:c.138+3367T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005546.4(ITK):​c.138+3367T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 152,094 control chromosomes in the GnomAD database, including 43,106 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (43106 hom., cov: 31)
• Consequence: ITK NM_005546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.173
• Publications: 8 publications found

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]

ITK Gene-Disease associations (from GenCC):

• lymphoproliferative syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• lymphoproliferative syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITK	NM_005546.4	c.138+3367T>C		intron_variant	Intron 1 of 16	ENST00000422843.8	NP_005537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITK	ENST00000422843.8	c.138+3367T>C		intron_variant	Intron 1 of 16	1	NM_005546.4	ENSP00000398655.4

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113869 AN: 151976 Hom.: 43057 Cov.: 31

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.747

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.749 AC: 113976 AN: 152094 Hom.: 43106 Cov.: 31 AF XY: 0.743 AC XY: 55262 AN XY: 74336

African (AFR) AF: 0.862 AC: 35768 AN: 41502

American (AMR) AF: 0.719 AC: 10989 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2306 AN: 3472

East Asian (EAS) AF: 0.641 AC: 3318 AN: 5174

South Asian (SAS) AF: 0.651 AC: 3136 AN: 4814

European-Finnish (FIN) AF: 0.683 AC: 7214 AN: 10558

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.718 AC: 48843 AN: 67990

Other (OTH) AF: 0.745 AC: 1570 AN: 2106

Alfa AF: 0.726 Hom.: 30089

Bravo AF: 0.759

Asia WGS AF: 0.669 AC: 2331 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.4
DANN	Benign	0.33
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs452223; hg19: chr5-156611493;