rs1554102738

Variant names:

• chr5-157240122-AT-A
• rs1554102738
• NM_005546.4:c.913delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005546.4(ITK):​c.913delT​(p.Tyr305ThrfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y305Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITK NM_005546.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.84
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-157240122-AT-A is Pathogenic according to our data. Variant chr5-157240122-AT-A is described in CliVar as Pathogenic. Clinvar id is 521210.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-157240122-AT-A is described in CliVar as Pathogenic. Clinvar id is 521210.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-157240122-AT-A is described in CliVar as Pathogenic. Clinvar id is 521210.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-157240122-AT-A is described in CliVar as Pathogenic. Clinvar id is 521210.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-157240122-AT-A is described in CliVar as Pathogenic. Clinvar id is 521210.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITK	NM_005546.4	c.913delT	p.Tyr305ThrfsTer27	frameshift_variant	Exon 10 of 17	ENST00000422843.8	NP_005537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITK	ENST00000422843.8	c.913delT	p.Tyr305ThrfsTer27	frameshift_variant	Exon 10 of 17	1	NM_005546.4	ENSP00000398655.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jul 28, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554102738; hg19: chr5-156667132;