chr4-141727982-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 14/22 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.

• 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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL15	NM_000585.5	c.238C>A	p.His80Asn	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000320650.9	NP_000576.1
IL15	NM_172175.3	c.157C>A	p.His53Asn	missense_variant, splice_region_variant	Exon 8 of 10		NP_751915.1
IL15	NR_037840.3	n.1101C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL15	ENST00000320650.9	c.238C>A	p.His80Asn	missense_variant, splice_region_variant	Exon 6 of 8	1	NM_000585.5	ENSP00000323505.4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000423

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000113

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;.;D;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.70	.;.;.;T;.;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M;M;.;M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.037	D;D;T;D;T;T
Sift4G	Benign	0.093	T;T;T;T;T;T
Polyphen		0.19	B;B;.;B;.;.
Vest4		0.48
MutPred		0.68		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-142649135;