21-44229931-A-G

Variant names:

• chr21-44229931-A-G
• rs200250197
• ENST00000400379.8:c.1021T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000400379.8(ICOSLG):​c.1021T>C​(p.Phe341Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. 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. F341I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 10)
• Consequence: ICOSLG ENST00000400379.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057094663).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000400379.8. 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.898+123T>C		intron	N/A	NP_056074.1	O75144-1
	ICOSLG	NM_001283050.2		c.898+123T>C		intron	N/A	NP_001269979.1	O75144-2
	ICOSLG	NM_001395918.1		c.898+123T>C		intron	N/A	NP_001382847.1	A0A8V8TQV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000400379.8	TSL:1	c.1021T>C	p.Phe341Leu	missense	Exon 6 of 6	ENSP00000383230.3	K4DIA0
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.898+123T>C		intron	N/A	ENSP00000384432.3	O75144-1
	ICOSLG	ENST00000344330.9	TSL:1	c.898+123T>C		intron	N/A	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 12

GnomAD4 genome Cov.: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
PhyloP100		-1.6
PromoterAI		-0.040	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200250197; hg19: chr21-45649814;