5-157244380-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_005546.4(ITK):c.1351C>T(p.Arg451Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

ITK
NM_005546.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.25

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38119936).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000164 (25/152194) while in subpopulation AMR AF= 0.000982 (15/15280). AF 95% confidence interval is 0.000605. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITK	NM_005546.4 link	c.1351C>T	p.Arg451Trp	missense_variant	Exon 13 of 17	ENST00000422843.8	NP_005537.3	Q08881

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITK	ENST00000422843.8 link	c.1351C>T	p.Arg451Trp	missense_variant	Exon 13 of 17	1	NM_005546.4	ENSP00000398655.4		Q08881

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251256

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000164

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000982

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.0000975

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ITK gene demonstrated a sequence change, c.1351C>T, in exon 13 that results in an amino acid change, p.Arg451Trp. This sequence change has been described in the gnomAD database with a frequency of 0.037% in the Latino/Admixed American subpopulation (dbSNP rs200331133). The p.Arg451Trp change affects a moderately conserved amino acid residue located in a domain of the ITK protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg451Trp substitution. This sequence change does not appear to have been previously described in individuals with ITK-related disorders. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg451Trp change remains unknown at this time. -

Inborn genetic diseases

Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1351C>T (p.R451W) alteration is located in exon 13 (coding exon 13) of the ITK gene. This alteration results from a C to T substitution at nucleotide position 1351, causing the arginine (R) at amino acid position 451 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

May 12, 2017

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lymphoproliferative syndrome 1

Uncertain:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 451 of the ITK protein (p.Arg451Trp). This variant is present in population databases (rs200331133, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ITK-related conditions. ClinVar contains an entry for this variant (Variation ID: 575120). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITK protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.39

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.54

MVP

0.85

MPC

1.2

ClinPred

0.51

GERP RS

3.3

Varity_R

0.72

gMVP

0.53

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