chr10-5956406-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002189.4(IL15RA):​c.665C>T​(p.Ser222Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IL15RA
NM_002189.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.779
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0688141).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IL15RANM_002189.4 linkuse as main transcriptc.665C>T p.Ser222Phe missense_variant 6/7 ENST00000379977.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IL15RAENST00000379977.8 linkuse as main transcriptc.665C>T p.Ser222Phe missense_variant 6/71 NM_002189.4 A2Q13261-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461778
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 17, 2024The c.665C>T (p.S222F) alteration is located in exon 6 (coding exon 6) of the IL15RA gene. This alteration results from a C to T substitution at nucleotide position 665, causing the serine (S) at amino acid position 222 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
0.63
DANN
Benign
0.90
DEOGEN2
Benign
0.0091
.;T;T;.;.;.;.;.;T;.;.;T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.0020
N
LIST_S2
Benign
0.71
T;D;T;T;T;D;D;D;T;T;T;T
M_CAP
Benign
0.0032
T
MetaRNN
Benign
0.069
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
.;.;N;.;.;.;.;.;.;.;N;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.070
.;.;N;.;.;N;N;N;.;N;N;.
REVEL
Benign
0.067
Sift
Benign
0.52
.;.;T;.;.;T;T;T;.;T;T;.
Sift4G
Benign
0.32
T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0
.;.;B;.;.;B;.;.;.;.;.;.
Vest4
0.13
MutPred
0.51
.;.;Gain of helix (P = 0.132);.;.;.;.;.;.;.;Gain of helix (P = 0.132);.;
MVP
0.27
MPC
0.41
ClinPred
0.028
T
GERP RS
-3.1
Varity_R
0.026
gMVP
0.13

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

LitVar

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

Other links and lift over

dbSNP: rs759647467; hg19: chr10-5998369; API