rs17054374

Positions:

chr5-157222945-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005546.4(ITK):c.578G>A(p.Arg193Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,614,094 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 5 hom., cov: 31)

Exomes 𝑓: 0.00046 ( 3 hom. )

Consequence

ITK
NM_005546.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.22

Variant links:

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 links:

ITK (HGNC:):

ITK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005519241).

BP6

Variant 5-157222945-G-A is Benign according to our data. Variant chr5-157222945-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 352464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00356 (542/152214) while in subpopulation AFR AF= 0.0122 (508/41546). AF 95% confidence interval is 0.0113. There are 5 homozygotes in gnomad4. There are 259 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITK	NM_005546.4 linkuse as main transcript	c.578G>A	p.Arg193Gln	missense_variant	6/17	ENST00000422843.8	NP_005537.3	Q08881

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITK	ENST00000422843.8 linkuse as main transcript	c.578G>A	p.Arg193Gln	missense_variant	6/17	1	NM_005546.4	ENSP00000398655.4		Q08881

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

538

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.000979

AC:

246

AN:

251378

Hom.:

AF XY:

0.000692

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000458

AC:

669

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

281

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0128

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000764

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00356

AC:

542

AN:

152214

Hom.:

Cov.:

AF XY:

0.00348

AC XY:

259

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0122

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.00435

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00119

AC:

144

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lymphoproliferative syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2022

- -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.3

DANN

Benign

0.70

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0055

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.82

.;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.11

Sift

Benign

0.76

T;T

Sift4G

Benign

0.85

T;T

Polyphen

0.0

.;B

Vest4

0.074

MVP

0.82

MPC

0.45

ClinPred

0.00087

GERP RS

-0.39

Varity_R

0.040

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over