chr5-157208987-G-A

Variant names:

• chr5-157208987-G-A
• rs201403794
• NM_005546.4:c.237G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005546.4(ITK):​c.237G>A​(p.Pro79Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,607,372 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: ITK NM_005546.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.88
• 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)

ENSG00000253980 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 5-157208987-G-A is Benign according to our data. Variant chr5-157208987-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 352458.
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000243 (37/152210) while in subpopulation SAS AF = 0.00104 (5/4816). AF 95% confidence interval is 0.000409. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.237G>A	p.Pro79Pro	synonymous	Exon 2 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.237G>A	p.Pro79Pro	synonymous	Exon 2 of 17	ENSP00000398655.4	Q08881
	ITK	ENST00000862614.1		c.237G>A	p.Pro79Pro	synonymous	Exon 2 of 17	ENSP00000532673.1
	ITK	ENST00000862615.1		c.234G>A	p.Pro78Pro	synonymous	Exon 2 of 17	ENSP00000532674.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000350 AC: 88 AN: 251204 AF XY: 0.000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000298 AC: 434 AN: 1455162 Hom.: 2 Cov.: 28 AF XY: 0.000330 AC XY: 239 AN XY: 724444

African (AFR) AF: 0.0000900 AC: 3 AN: 33340

American (AMR) AF: 0.000291 AC: 13 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26080

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39646

South Asian (SAS) AF: 0.000941 AC: 81 AN: 86120

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53406

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5750

European-Non Finnish (NFE) AF: 0.000241 AC: 266 AN: 1105916

Other (OTH) AF: 0.000432 AC: 26 AN: 60186

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152210 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18 AN XY: 74410

African (AFR) AF: 0.000120 AC: 5 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68002

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000223

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.8
DANN	Benign	0.78
PhyloP100		-1.9
Mutation Taster		=100/0	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: rs201403794; hg19: chr5-156635998; COSMIC: COSV70060419;