chr5-157248957-C-T

Position:

chr5-157248957-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005546.4(ITK):c.1741C>T(p.Arg581Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,613,884 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 2 hom. )

Consequence

ITK
NM_005546.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.80

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016388476).

BP6

Variant 5-157248957-C-T is Benign according to our data. Variant chr5-157248957-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 352476.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000453 (69/152274) while in subpopulation EAS AF= 0.00521 (27/5182). AF 95% confidence interval is 0.00368. There are 1 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITK	NM_005546.4 linkuse as main transcript	c.1741C>T	p.Arg581Trp	missense_variant	16/17	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.1741C>T	p.Arg581Trp	missense_variant	16/17	1	NM_005546.4	ENSP00000398655.4		Q08881

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00520

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000980

AC:

246

AN:

251100

Hom.:

AF XY:

0.000929

AC XY:

126

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.00739

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000389

AC:

568

AN:

1461610

Hom.:

Cov.:

AF XY:

0.000407

AC XY:

296

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00654

Gnomad4 EAS exome

AF:

0.00438

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.000453

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00521

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000658

Hom.:

Bravo

AF:

0.000540

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ITK: PM5, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	Identified in individuals with hemophagocytic lymphohistiocytosis in the published literature, however, no additional information was provided (Miao et al., 2019); Identified in the heterozygous state in patients with primary Sjogren's syndrome and with natural killer/T-cell lymphoma in the published literature, however, this variant was also identified in unaffected individuals in these families (Wang et al., 2020; Li et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24448499, 31848144, 32874983, 30899265) -

Lymphoproliferative syndrome 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2018

- -

ITK-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.79

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.081

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.41

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.48

MVP

0.94

MPC

0.97

ClinPred

0.15

GERP RS

4.8

Varity_R

0.87

gMVP

0.77

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