rs1165558487

Variant names:

• chr21-44238447-C-A
• rs1165558487
• NM_015259.6:c.55+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-44238447-C-A
• chr21-44238447-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_015259.6(ICOSLG):​c.55+1G>T variant causes a splice donor, intron change. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: ICOSLG NM_015259.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.96
• Publications: 0 publications found

Genes affected

ICOSLG (HGNC:17087): (inducible T cell costimulator ligand) Enables identical protein binding activity. Predicted to be involved in T cell receptor signaling pathway and positive regulation of interleukin-4 production. Located in cytoplasmic ribonucleoprotein granule and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ICOSLG Gene-Disease associations (from GenCC):

• combined immunodeficiency

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• immunodeficiency 119

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 21-44238447-C-A is Pathogenic according to our data. Variant chr21-44238447-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522117.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015259.6. 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
	ICOSLG	NM_015259.6	MANE Select	c.55+1G>T		splice_donor intron	N/A	NP_056074.1	O75144-1
	ICOSLG	NM_001283050.2		c.55+1G>T		splice_donor intron	N/A	NP_001269979.1	O75144-2
	ICOSLG	NM_001395918.1		c.55+1G>T		splice_donor intron	N/A	NP_001382847.1	A0A8V8TQV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.55+1G>T		splice_donor intron	N/A	ENSP00000384432.3	O75144-1
	ICOSLG	ENST00000400379.8	TSL:1	c.55+1G>T		splice_donor intron	N/A	ENSP00000383230.3	K4DIA0
	ICOSLG	ENST00000344330.9	TSL:1	c.55+1G>T		splice_donor intron	N/A	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	29
DANN	Uncertain	0.98
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.77	D
PhyloP100		4.0
Mutation Taster		=33/67	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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.

Other links and lift over

dbSNP: rs1165558487;

hg19: chr21-45658330;