10-5953184-C-A

Variant names:

• chr10-5953184-C-A
• rs141171117
• NM_002189.4:c.715G>T
• IL15RA p.Val239Phe

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_002189.4(IL15RA):c.715G>T (p.Val239Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,814 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000252. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V239I: Benign (ClinVar VariationId 709069, 2 stars)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL15RA NM_002189.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.613
• Publications: 3 publications found

Genes affected

IL15RA (HGNC:5978): (interleukin 15 receptor subunit alpha) This gene encodes a cytokine receptor that specifically binds interleukin 15 (IL15) with high affinity. The receptors of IL15 and IL2 share two subunits, IL2R beta and IL2R gamma. This forms the basis of many overlapping biological activities of IL15 and IL2. The protein encoded by this gene is structurally related to IL2R alpha, an additional IL2-specific alpha subunit necessary for high affinity IL2 binding. Unlike IL2RA, IL15RA is capable of binding IL15 with high affinity independent of other subunits, which suggests distinct roles between IL15 and IL2. This receptor is reported to enhance cell proliferation and expression of apoptosis inhibitor BCL2L1/BCL2-XL and BCL2. Multiple alternatively spliced transcript variants of this gene have been reported.[provided by RefSeq, Apr 2010]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000252 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002189.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL15RA NM_002189.4	MANE Select	c.715G>T p.Val239Phe	missense	Exon 7 of 7	Prot: NP_002180.1 UniProt:
	IL15RA NM_001256765.1		c.973G>T p.Val325Phe	missense	Exon 8 of 8	Prot: NP_001243694.1 UniProt:
	IL15RA NM_172200.3		c.616G>T p.Val206Phe	missense	Exon 6 of 6	Prot: NP_751950.2 UniProt:

IL15RA NM_002189.4

MANE Select

HGVSc / HGVSpc.715G>Tp.Val239Phe

Exon rankExon 7 of 7

missense

Prot: NP_002180.1UniProt: Q13261-1

IL15RA NM_001256765.1

HGVSc / HGVSpc.973G>Tp.Val325Phe

Exon rankExon 8 of 8

missense

Prot: NP_001243694.1UniProt: Q13261G8CVM3A0A0A0MS77

IL15RA NM_172200.3

HGVSc / HGVSpc.616G>Tp.Val206Phe

Exon rankExon 6 of 6

missense

Prot: NP_751950.2UniProt: Q13261-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL15RA ENST00000379977.8	TSL:1MANE Select	c.715G>T p.Val239Phe	missense	Exon 7 of 7	Prot: ENSP00000369312.3 UniProt:
	IL15RA ENST00000397248.6	TSL:1	c.973G>T p.Val325Phe	missense	Exon 8 of 8	Prot: ENSP00000380421.3 UniProt:
	IL15RA ENST00000525219.6	TSL:1	c.607G>T p.Val203Phe	missense	Exon 7 of 7	Prot: ENSP00000431529.2 UniProt:

IL15RA ENST00000379977.8

TSL:1MANE Select

HGVSc / HGVSpc.715G>Tp.Val239Phe

Exon rankExon 7 of 7

missense

Prot: ENSP00000369312.3UniProt: Q13261-1

IL15RA ENST00000397248.6

TSL:1

HGVSc / HGVSpc.973G>Tp.Val325Phe

Exon rankExon 8 of 8

missense

Prot: ENSP00000380421.3UniProt: A0A0A0MS77

IL15RA ENST00000525219.6

TSL:1

HGVSc / HGVSpc.607G>Tp.Val203Phe

Exon rankExon 7 of 7

missense

Prot: ENSP00000431529.2UniProt: Q13261-10

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.00000803	AC:2	Hom:	AN:249130	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461814	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
Local & regional cohorts 2 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7234	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000617	3	48592	0.0000401	3	74798

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	11
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.5
DANN	Benign	0.96
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
FuncVEP CTI	Benign	0.074
GPN-Star LLR	N/A	-3.1
GPN-Star score	N/A	3.1
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.98	T
Mutation Taster	N/A	94/6	polymorphism
MutationAssessor	Benign	1.6	L
PhyloP100	Benign	-0.61
popEVE	Benign	-3.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.4	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.0
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.028	D
Varity_R	N/A	0.081
VESM-3B	Benign	-8.1

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs141171117;

hg19: chr10-5995147;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar