rs753746979

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000585.5(IL15):c.218T>C(p.Leu73Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,360,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

IL15
NM_000585.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.53

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL15	NM_000585.5	MANE Select	c.218T>C	p.Leu73Ser	missense	Exon 6 of 8	NP_000576.1	P40933-1
IL15	NM_172175.3		c.137T>C	p.Leu46Ser	missense	Exon 8 of 10	NP_751915.1	P40933-2
IL15	NR_037840.3		n.1081T>C		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL15	ENST00000320650.9	TSL:1 MANE Select	c.218T>C	p.Leu73Ser	missense	Exon 6 of 8	ENSP00000323505.4	P40933-1
IL15	ENST00000296545.11	TSL:1	c.218T>C	p.Leu73Ser	missense	Exon 6 of 8	ENSP00000296545.7	P40933-1
IL15	ENST00000394159.2	TSL:1	c.137T>C	p.Leu46Ser	missense	Exon 3 of 5	ENSP00000377714.1	P40933-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000589

AC:

AN:

220884

AF XY:

0.0000834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000193

GnomAD4 exome

AF:

0.0000339

AC:

AN:

1208162

Hom.:

Cov.:

AF XY:

0.0000458

AC XY:

AN XY:

611552

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27262

American (AMR)

AF:

0.00

AC:

AN:

36552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24002

East Asian (EAS)

AF:

0.00

AC:

AN:

36918

South Asian (SAS)

AF:

0.00

AC:

AN:

74868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4746

European-Non Finnish (NFE)

AF:

0.0000456

AC:

AN:

899684

Other (OTH)

AF:

0.00

AC:

AN:

51468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000779

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000577

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.80

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.023

MutationAssessor

Uncertain

2.5

PhyloP100

3.5

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.85

Gain of disorder (P = 0.002)

MVP

0.79

MPC

0.16

ClinPred

0.73

GERP RS

4.7

Varity_R

0.87

gMVP

0.65

Mutation Taster

=56/44

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over