rs56005928

chr5-157248975-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005546.4(ITK):c.1759G>A(p.Val587Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,613,900 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (34 hom.)
• Consequence: ITK NM_005546.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0170

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076246858).
• BP6: Variant 5-157248975-G-A is Benign according to our data. Variant chr5-157248975-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 522219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-157248975-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0033 (503/152300) while in subpopulation SAS AF= 0.00332 (16/4826). AF 95% confidence interval is 0.0027. There are 3 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITK	NM_005546.4	c.1759G>A	p.Val587Ile	missense_variant	16/17	ENST00000422843.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITK	ENST00000422843.8	c.1759G>A	p.Val587Ile	missense_variant	16/17	1	NM_005546.4	P1
ITK	ENST00000519749.1	n.764G>A		non_coding_transcript_exon_variant	5/6	1
ITK	ENST00000519402.5	n.3344G>A		non_coding_transcript_exon_variant	15/16	2
ITK	ENST00000696962.1	c.*536G>A		3_prime_UTR_variant, NMD_transcript_variant	15/16

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 152182 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00402 AC: 1009 AN: 251032 Hom.: 9 AF XY: 0.00426 AC XY: 578 AN XY: 135664

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.000924

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.00278

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00271 AC: 3963 AN: 1461600 Hom.: 34 Cov.: 32 AF XY: 0.00285 AC XY: 2072 AN XY: 727112

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00330 AC: 503 AN: 152300 Hom.: 3 Cov.: 33 AF XY: 0.00426 AC XY: 317 AN XY: 74460

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0212

Gnomad4 NFE AF: 0.00304

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00330 Hom.: 5

Bravo AF: 0.00163

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00342 AC: 415

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lymphoproliferative syndrome 1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Dec 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 06, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

ITK: BP4, BS2 -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	4.8
Dann	Benign	0.77
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.51	N
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.11
Sift	Benign	0.77	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.53
MPC		0.33
ClinPred		0.00051	T
GERP RS		0.28
Varity_R		0.058
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

LitVar

Other links and lift over

dbSNP: rs56005928; hg19: chr5-156675985;