rs121908191

Variant names:

• chr5-157241663-C-T
• rs121908191
• NM_005546.4:c.1003C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-157241663-C-T
• chr5-157241663-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PP3 PP5_Moderate

The NM_005546.4(ITK):​c.1003C>T​(p.Arg335Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005834987: Experimental studies have shown that this missense change affects ITK function (PMID:22289921).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITK NM_005546.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.217
• Publications: 15 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005834987: Experimental studies have shown that this missense change affects ITK function (PMID: 22289921).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833
• PP5: Variant 5-157241663-C-T is Pathogenic according to our data. Variant chr5-157241663-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 12741.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005546.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITK	NM_005546.4	MANE Select	c.1003C>T	p.Arg335Trp	missense	Exon 11 of 17	NP_005537.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITK	ENST00000422843.8	TSL:1 MANE Select	c.1003C>T	p.Arg335Trp	missense	Exon 11 of 17	ENSP00000398655.4	Q08881
	ITK	ENST00000519749.1	TSL:1	n.73C>T		non_coding_transcript_exon	Exon 1 of 6
	ITK	ENST00000862614.1		c.1003C>T	p.Arg335Trp	missense	Exon 11 of 17	ENSP00000532673.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461588 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111788

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000653 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Lymphoproliferative syndrome 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.22
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.41
MutPred		0.81		Loss of methylation at R333 (P = 0.073)
MVP		0.83
MPC		1.2
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.75
gMVP		0.83
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908191; hg19: chr5-156668673;