chr5-157244427-G-T

Variant names:

• chr5-157244427-G-T
• rs17595896
• NM_005546.4:c.1398G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005546.4(ITK):​c.1398G>T​(p.Val466Val) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V466V) has been classified as Likely 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
• Publications: 4 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: Benign. The variant received -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 VariationId is 540360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1398G>T	p.Val466Val	synonymous	Exon 13 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.1398G>T	p.Val466Val	synonymous	Exon 13 of 17	ENSP00000398655.4	Q08881
	ITK	ENST00000519749.1	TSL:1	n.468G>T		non_coding_transcript_exon	Exon 3 of 6
	ITK	ENST00000862614.1		c.1398G>T	p.Val466Val	synonymous	Exon 13 of 17	ENSP00000532673.1

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

GnomAD2 exomes AF: 0.00880 AC: 2210 AN: 251180 AF XY: 0.0103

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 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

African (AFR) AF: 0.00105 AC: 35 AN: 33474

American (AMR) AF: 0.00731 AC: 327 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 548 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0264 AC: 2275 AN: 86252

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53412

Middle Eastern (MID) AF: 0.0473 AC: 273 AN: 5768

European-Non Finnish (NFE) AF: 0.00470 AC: 5222 AN: 1111876

Other (OTH) AF: 0.00924 AC: 558 AN: 60388

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

African (AFR) AF: 0.00101 AC: 42 AN: 41582

American (AMR) AF: 0.0110 AC: 169 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0246 AC: 119 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00651 AC: 443 AN: 68022

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00671 Hom.: 17

Bravo AF: 0.00572

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00987

EpiControl AF: 0.0102

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Lymphoproliferative syndrome 1 (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.7
DANN	Benign	0.76
PhyloP100		2.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs17595896; hg19: chr5-156671437;