5-157244427-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005546.4(ITK):c.1398G>T(p.Val466=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,614,044 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (121 hom.)
• Consequence: ITK NM_005546.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 5-157244427-G-T is Benign according to our data. Variant chr5-157244427-G-T is described in ClinVar as [Benign]. Clinvar id is 540360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-157244427-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00577 (879/152320) while in subpopulation SAS AF= 0.0246 (119/4830). AF 95% confidence interval is 0.021. There are 6 homozygotes in gnomad4. There are 449 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITK	NM_005546.4	c.1398G>T	p.Val466=	synonymous_variant	13/17	ENST00000422843.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITK	ENST00000422843.8	c.1398G>T	p.Val466=	synonymous_variant	13/17	1	NM_005546.4	P1
ITK	ENST00000519749.1	n.468G>T		non_coding_transcript_exon_variant	3/6	1
ITK	ENST00000519402.5	n.2983G>T		non_coding_transcript_exon_variant	12/16	2
ITK	ENST00000696962.1	c.*175G>T		3_prime_UTR_variant, NMD_transcript_variant	12/16

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 877 AN: 152202 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00650

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00880 AC: 2210 AN: 251180 Hom.: 39 AF XY: 0.0103 AC XY: 1400 AN XY: 135738

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0271

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00695

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.00634 AC: 9272 AN: 1461724 Hom.: 121 Cov.: 32 AF XY: 0.00718 AC XY: 5219 AN XY: 727174

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00731

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0264

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00470

Gnomad4 OTH exome AF: 0.00924

GnomAD4 genome AF: 0.00577 AC: 879 AN: 152320 Hom.: 6 Cov.: 32 AF XY: 0.00603 AC XY: 449 AN XY: 74486

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0246

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00651

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00705 Hom.: 14

Bravo AF: 0.00572

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00987

EpiControl AF: 0.0102

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lymphoproliferative syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 13, 2018

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	7.7
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17595896; hg19: chr5-156671437;