NM_000585.5:c.12+8A>G

Variant names:

• chr4-141719484-A-G
• rs2857261
• NM_000585.5:c.12+8A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Publications: 21 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000585.5. 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
	IL15	NM_000585.5	MANE Select	c.12+8A>G		splice_region intron	N/A	NP_000576.1	P40933-1
	IL15	NM_172175.3		c.-189+8A>G		splice_region intron	N/A	NP_751915.1	P40933-2
	IL15	NR_037840.3		n.875+8A>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL15	ENST00000320650.9	TSL:1 MANE Select	c.12+8A>G		splice_region intron	N/A	ENSP00000323505.4	P40933-1
	IL15	ENST00000296545.11	TSL:1	c.12+8A>G		splice_region intron	N/A	ENSP00000296545.7	P40933-1
	IL15	ENST00000477265.5	TSL:1	c.-189+8A>G		splice_region intron	N/A	ENSP00000436914.1	P40933-2

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73679 AN: 151816 Hom.: 17913 Cov.: 31

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

GnomAD2 exomes AF: 0.479 AC: 114231 AN: 238246 AF XY: 0.485

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 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.: 16 AF XY: 0.460 AC XY: 248805 AN XY: 541118

African (AFR) AF: 0.455 AC: 11448 AN: 25178

American (AMR) AF: 0.362 AC: 15254 AN: 42128

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 12482 AN: 23096

East Asian (EAS) AF: 0.491 AC: 18127 AN: 36884

South Asian (SAS) AF: 0.558 AC: 41637 AN: 74630

European-Finnish (FIN) AF: 0.553 AC: 29215 AN: 52804

Middle Eastern (MID) AF: 0.415 AC: 2050 AN: 4938

European-Non Finnish (NFE) AF: 0.437 AC: 326484 AN: 747464

Other (OTH) AF: 0.459 AC: 21386 AN: 46566

GnomAD4 genome AF: 0.485 AC: 73722 AN: 151936 Hom.: 17924 Cov.: 31 AF XY: 0.490 AC XY: 36401 AN XY: 74242

African (AFR) AF: 0.487 AC: 20194 AN: 41424

American (AMR) AF: 0.432 AC: 6601 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1945 AN: 3460

East Asian (EAS) AF: 0.529 AC: 2726 AN: 5150

South Asian (SAS) AF: 0.592 AC: 2854 AN: 4818

European-Finnish (FIN) AF: 0.555 AC: 5863 AN: 10570

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31918 AN: 67932

Other (OTH) AF: 0.468 AC: 986 AN: 2106

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2857261; hg19: chr4-142640637; COSMIC: COSV56724678; COSMIC: COSV56724678;