rs769020860

Variant names:

• chr4-141727982-C-A
• rs769020860
• NM_000585.5:c.238C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-141727982-C-A
• chr4-141727982-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000585.5(IL15):​c.238C>A​(p.His80Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,189,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H80Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: IL15 NM_000585.5 missense, splice_region
• Scores: Splicing: ADA: 0.0002559
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.898
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32223558).

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.238C>A	p.His80Asn	missense splice_region	Exon 6 of 8	NP_000576.1	P40933-1
	IL15	NM_172175.3		c.157C>A	p.His53Asn	missense splice_region	Exon 8 of 10	NP_751915.1	P40933-2
	IL15	NR_037840.3		n.1101C>A		splice_region non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL15	ENST00000320650.9	TSL:1 MANE Select	c.238C>A	p.His80Asn	missense splice_region	Exon 6 of 8	ENSP00000323505.4	P40933-1
	IL15	ENST00000296545.11	TSL:1	c.238C>A	p.His80Asn	missense splice_region	Exon 6 of 8	ENSP00000296545.7	P40933-1
	IL15	ENST00000394159.2	TSL:1	c.157C>A	p.His53Asn	missense splice_region	Exon 3 of 5	ENSP00000377714.1	P40933-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000168 AC: 2 AN: 1189246 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 602522

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26608

American (AMR) AF: 0.00 AC: 0 AN: 35116

Ashkenazi Jewish (ASJ) AF: 0.0000423 AC: 1 AN: 23638

East Asian (EAS) AF: 0.00 AC: 0 AN: 36870

South Asian (SAS) AF: 0.00 AC: 0 AN: 73960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4512

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 885284

Other (OTH) AF: 0.00 AC: 0 AN: 50738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.90
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.16
Sift	Benign	0.037	D
Sift4G	Benign	0.093	T
Polyphen		0.19	B
Vest4		0.48
MutPred		0.68		Gain of sheet (P = 0.0477)
MVP		0.46
MPC		0.024
ClinPred		0.27	T
GERP RS		2.9
Varity_R		0.37
gMVP		0.096
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.026
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

Other links and lift over

dbSNP: rs769020860; hg19: chr4-142649135;