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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOSLG	NM_015259.6	c.55+1G>T		splice_donor_variant, intron_variant	Intron 2 of 6	ENST00000407780.8	NP_056074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOSLG	ENST00000407780.8	c.55+1G>T		splice_donor_variant, intron_variant	Intron 2 of 6	1	NM_015259.6	ENSP00000384432.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 27, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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
GERP RS		3.3
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

Other links and lift over

dbSNP: rs1165558487; hg19: chr21-45658330;