rs55646940

chr5-157238099-A-T

Variant summary

Our verdict is Benign. Variant got -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 splice polypyrimidine tract, 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (28 hom., cov: 32)
  • Exomes 𝑓: 0.025 (578 hom.)
• Consequence: ITK NM_005546.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000005349
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.678

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITK	NM_005546.4	c.769-10A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000422843.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITK	ENST00000422843.8	c.769-10A>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005546.4	P1
ITK	ENST00000696962.1	c.769-10A>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant
ITK	ENST00000519402.5	n.904-10A>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
ITK	ENST00000519759.1	n.388-10A>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes AF: 0.0172 AC: 4317 AN: 251268 Hom.: 71 AF XY: 0.0172 AC XY: 2336 AN XY: 135798

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

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.: 28 Cov.: 32 AF XY: 0.0163 AC XY: 1211 AN XY: 74452

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.: 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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 05, 2015	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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	16
Dann	Benign	0.78

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

Other links and lift over

dbSNP: rs55646940; hg19: chr5-156665109;