Genetic Variant IL15:c.12+8A>G (chr4-141719484-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000585.5(IL15):c.12+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 1,205,624 control chromosomes in the GnomAD database, including 128,776 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 17924 hom., cov: 31)

Exomes 𝑓: 0.45 ( 110852 hom. )

Consequence

IL15
NM_000585.5 splice_region, intron

Scores

Splicing: ADA: 0.0003365

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.497

Variant links:

Genes affected

IL15 (HGNC:5977): (interleukin 15) The protein encoded by this gene is a cytokine that regulates T and natural killer cell activation and proliferation. This cytokine and interleukine 2 share many biological activities. They are found to bind common hematopoietin receptor subunits, and may compete for the same receptor, and thus negatively regulate each other's activity. The number of CD8+ memory cells is shown to be controlled by a balance between this cytokine and IL2. This cytokine induces the activation of JAK kinases, as well as the phosphorylation and activation of transcription activators STAT3, STAT5, and STAT6. Studies of the mouse counterpart suggested that this cytokine may increase the expression of apoptosis inhibitor BCL2L1/BCL-x(L), possibly through the transcription activation activity of STAT6, and thus prevent apoptosis. Alternatively spliced transcript variants of this gene have been reported. [provided by RefSeq, Feb 2011]

IL15 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
IL15	NM_000585.5 link	c.12+8A>G	splice_region_variant, intron_variant	Intron 3 of 7	ENST00000320650.9	NP_000576.1	P40933-1
IL15	NM_172175.3 link	c.-189+8A>G	splice_region_variant, intron_variant	Intron 4 of 9		NP_751915.1	P40933-2
IL15	NR_037840.3 link	n.875+8A>G	splice_region_variant, intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL15	ENST00000320650.9 link	c.12+8A>G		splice_region_variant, intron_variant	Intron 3 of 7	1	NM_000585.5	ENSP00000323505.4		P40933-1

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73679

AN:

151816

Hom.:

17913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.558

Gnomad AMR

AF:

0.432

Gnomad ASJ

AF:

0.562

Gnomad EAS

AF:

0.529

Gnomad SAS

AF:

0.592

Gnomad FIN

AF:

0.555

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.470

Gnomad OTH

AF:

0.465

GnomAD3 exomes

AF:

0.479

AC:

114231

AN:

238246

Hom.:

28097

AF XY:

0.485

AC XY:

62469

AN XY:

128816

show subpopulations

Gnomad AFR exome

AF:

0.477

Gnomad AMR exome

AF:

0.353

Gnomad ASJ exome

AF:

0.547

Gnomad EAS exome

AF:

0.523

Gnomad SAS exome

AF:

0.567

Gnomad FIN exome

AF:

0.552

Gnomad NFE exome

AF:

0.467

Gnomad OTH exome

AF:

0.478

GnomAD4 exome

AF:

0.454

AC:

478083

AN:

1053688

Hom.:

110852

Cov.:

AF XY:

0.460

AC XY:

248805

AN XY:

541118

show subpopulations

Gnomad4 AFR exome

AF:

0.455

Gnomad4 AMR exome

AF:

0.362

Gnomad4 ASJ exome

AF:

0.540

Gnomad4 EAS exome

AF:

0.491

Gnomad4 SAS exome

AF:

0.558

Gnomad4 FIN exome

AF:

0.553

Gnomad4 NFE exome

AF:

0.437

Gnomad4 OTH exome

AF:

0.459

GnomAD4 genome

AF:

0.485

AC:

73722

AN:

151936

Hom.:

17924

Cov.:

AF XY:

0.490

AC XY:

36401

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.487

Gnomad4 AMR

AF:

0.432

Gnomad4 ASJ

AF:

0.562

Gnomad4 EAS

AF:

0.529

Gnomad4 SAS

AF:

0.592

Gnomad4 FIN

AF:

0.555

Gnomad4 NFE

AF:

0.470

Gnomad4 OTH

AF:

0.468

Alfa

AF:

0.479

Hom.:

5597

Bravo

AF:

0.472

Asia WGS

AF:

0.574

AC:

1994

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00034

dbscSNV1_RF

Benign

0.0060

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over