10-5963793-G-A

Position:

• chr10-5963793-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002189.4(IL15RA):​c.332C>T​(p.Thr111Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 1,535,744 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (40 hom.)
• Consequence: IL15RA NM_002189.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.128

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]

LOC107984200 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 10-5963793-G-A is Benign according to our data. Variant chr10-5963793-G-A is described in ClinVar as [Benign]. Clinvar id is 770960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00371 (565/152276) while in subpopulation EAS AF= 0.0215 (111/5170). AF 95% confidence interval is 0.0182. There are 3 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL15RA	NM_002189.4	c.332C>T	p.Thr111Met	missense_variant	3/7	ENST00000379977.8	NP_002180.1
LOC107984200	XR_001747348.2	n.1321-391G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL15RA	ENST00000379977.8	c.332C>T	p.Thr111Met	missense_variant	3/7	1	NM_002189.4	ENSP00000369312	A2

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 565 AN: 152158 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00528

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00394 AC: 708 AN: 179836 Hom.: 6 AF XY: 0.00353 AC XY: 351 AN XY: 99426

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.000380

Gnomad ASJ exome AF: 0.000271

Gnomad EAS exome AF: 0.0223

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.000494

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00561 AC: 7762 AN: 1383468 Hom.: 40 Cov.: 31 AF XY: 0.00543 AC XY: 3729 AN XY: 686700

Gnomad4 AFR exome AF: 0.00100

Gnomad4 AMR exome AF: 0.000637

Gnomad4 ASJ exome AF: 0.000508

Gnomad4 EAS exome AF: 0.0210

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.000605

Gnomad4 NFE exome AF: 0.00613

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.00371 AC: 565 AN: 152276 Hom.: 3 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74464

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0215

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00528

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00471 Hom.: 3

Bravo AF: 0.00420

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00392 AC: 476

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	.;T;T;.;.;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.71	T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L;.;.;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.64	.;.;N;N;.;N;.;.;N
REVEL	Benign	0.031
Sift	Benign	0.075	.;.;T;D;.;T;.;.;T
Sift4G	Uncertain	0.016	D;D;T;D;D;D;D;D;T
Polyphen		0.13	.;.;B;.;.;.;.;.;.
Vest4		0.18
MVP		0.13
MPC		0.54
ClinPred		0.011	T
GERP RS		-2.3
Varity_R		0.015
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 48

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

Publications

LitVar

Other links and lift over

dbSNP: rs41294171; hg19: chr10-6005756; COSMIC: COSV66093013; COSMIC: COSV66093013;