rs121908191

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ITK
NM_005546.4 missense

Scores

9
8
2

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 0.217
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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 [Pathogenic]. Clinvar id is 12741.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ITKNM_005546.4 linkuse as main transcriptc.1003C>T p.Arg335Trp missense_variant 11/17 ENST00000422843.8 NP_005537.3 Q08881

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ITKENST00000422843.8 linkuse as main transcriptc.1003C>T p.Arg335Trp missense_variant 11/171 NM_005546.4 ENSP00000398655.4 Q08881

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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Lymphoproliferative syndrome 1 Pathogenic:1Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2012- -

Computational scores

Source: dbNSFP v4.3

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
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

Splicing

Name
Calibrated prediction
Score
Prediction
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908191; hg19: chr5-156668673; API