rs55646940

Positions:

chr5-157238099-A-T

Variant summary

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

The NM_005546.4(ITK):c.769-10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0244 in 1,606,484 control chromosomes in the GnomAD database, including 606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.018 ( 28 hom., cov: 32)

Exomes 𝑓: 0.025 ( 578 hom. )

Consequence

ITK
NM_005546.4 intron

Scores

Splicing: ADA: 0.000005349

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.678

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

This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 5-157238099-A-T is Benign according to our data. Variant chr5-157238099-A-T is described in ClinVar as [Benign]. Clinvar id is 352467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-157238099-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2684/152250) while in subpopulation NFE AF= 0.0271 (1845/68030). AF 95% confidence interval is 0.0261. There are 28 homozygotes in gnomad4. There are 1211 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITK	NM_005546.4 linkuse as main transcript	c.769-10A>T		intron_variant		ENST00000422843.8	NP_005537.3	Q08881

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
ITK	ENST00000422843.8 linkuse as main transcript	c.769-10A>T	intron_variant	1	NM_005546.4	ENSP00000398655.4	Q08881
ITK	ENST00000519402.5 linkuse as main transcript	n.904-10A>T	intron_variant	2
ITK	ENST00000519759.1 linkuse as main transcript	n.388-10A>T	intron_variant	4
ITK	ENST00000696962.1 linkuse as main transcript	n.769-10A>T	intron_variant			ENSP00000513001.1	A0A8V8TLR2

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2683

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00852

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0172

AC:

4317

AN:

251268

Hom.:

AF XY:

0.0172

AC XY:

2336

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00849

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00261

Gnomad FIN exome

AF:

0.0244

Gnomad NFE exome

AF:

0.0285

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.0251

AC:

36500

AN:

1454234

Hom.:

578

Cov.:

AF XY:

0.0243

AC XY:

17599

AN XY:

724070

show subpopulations

Gnomad4 AFR exome

AF:

0.00727

Gnomad4 AMR exome

AF:

0.00530

Gnomad4 ASJ exome

AF:

0.00567

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00315

Gnomad4 FIN exome

AF:

0.0256

Gnomad4 NFE exome

AF:

0.0299

Gnomad4 OTH exome

AF:

0.0191

GnomAD4 genome

AF:

0.0176

AC:

2684

AN:

152250

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1211

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00857

Gnomad4 AMR

AF:

0.00732

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0254

Gnomad4 NFE

AF:

0.0271

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0164

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lymphoproliferative syndrome 1

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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. -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.78

BranchPoint Hunter

3.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000053

dbscSNV1_RF

Benign

0.036

SpliceAI score (max)

0.090

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