rs140542010

Variant names:

• chr5-157248931-G-A
• rs140542010
• NM_005546.4:c.1715G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-157248931-G-A
• chr5-157248931-G-C
• chr5-157248931-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005546.4(ITK):​c.1715G>A​(p.Ser572Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S572S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITK NM_005546.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0600
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1873165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITK	NM_005546.4	c.1715G>A	p.Ser572Asn	missense_variant	Exon 16 of 17	ENST00000422843.8	NP_005537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITK	ENST00000422843.8	c.1715G>A	p.Ser572Asn	missense_variant	Exon 16 of 17	1	NM_005546.4	ENSP00000398655.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1715G>A (p.S572N) alteration is located in exon 16 (coding exon 16) of the ITK gene. This alteration results from a G to A substitution at nucleotide position 1715, causing the serine (S) at amino acid position 572 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Lymphoproliferative syndrome 1 Uncertain:1

Jul 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with asparagine at codon 572 of the ITK protein (p.Ser572Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ITK-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.060
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Benign	0.17	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.54		Loss of glycosylation at S572 (P = 0.0946);
MVP		0.89
MPC		0.37
ClinPred		0.18	T
GERP RS		3.9
Varity_R		0.32
gMVP		0.34
Mutation Taster		=80/20	polymorphism

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: rs140542010; hg19: chr5-156675941;