rs55646940

Variant names:

• chr5-157238099-A-T
• rs55646940
• NM_005546.4:c.769-10A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• lymphoproliferative syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• lymphoproliferative syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId is 352467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITK	NM_005546.4	c.769-10A>T		intron_variant	Intron 8 of 16	ENST00000422843.8	NP_005537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITK	ENST00000422843.8	c.769-10A>T		intron_variant	Intron 8 of 16	1	NM_005546.4	ENSP00000398655.4
ITK	ENST00000519402.5	n.904-10A>T		intron_variant	Intron 8 of 15	2
ITK	ENST00000519759.1	n.388-10A>T		intron_variant	Intron 3 of 4	4
ITK	ENST00000696962.1	n.769-10A>T		intron_variant	Intron 8 of 15			ENSP00000513001.1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2683 AN: 152132 Hom.: 28 Cov.: 32

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

GnomAD2 exomes AF: 0.0172 AC: 4317 AN: 251268 AF XY: 0.0172

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 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.: 29 AF XY: 0.0243 AC XY: 17599 AN XY: 724070

African (AFR) AF: 0.00727 AC: 242 AN: 33296

American (AMR) AF: 0.00530 AC: 237 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00567 AC: 148 AN: 26080

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.00315 AC: 271 AN: 86138

European-Finnish (FIN) AF: 0.0256 AC: 1366 AN: 53386

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5758

European-Non Finnish (NFE) AF: 0.0299 AC: 33079 AN: 1105104

Other (OTH) AF: 0.0191 AC: 1147 AN: 60124

GnomAD4 genome AF: 0.0176 AC: 2684 AN: 152250 Hom.: 28 Cov.: 32 AF XY: 0.0163 AC XY: 1211 AN XY: 74452

African (AFR) AF: 0.00857 AC: 356 AN: 41530

American (AMR) AF: 0.00732 AC: 112 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.0254 AC: 269 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0271 AC: 1845 AN: 68030

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0194 Hom.: 4

Bravo AF: 0.0164

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lymphoproliferative syndrome 1 Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 21, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.78
PhyloP100		0.68
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55646940; hg19: chr5-156665109;