chr21-44229039-C-T

Variant names:

• chr21-44229039-C-T
• rs780312517
• NM_015259.6:c.904G>A

Variant summary

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

The NM_015259.6(ICOSLG):​c.904G>A​(p.Val302Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000056 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000013 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOSLG NM_015259.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.765
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058698922).

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.904G>A	p.Val302Ile	missense	Exon 7 of 7	NP_056074.1	O75144-1
	ICOSLG	NM_001365759.2		c.823G>A	p.Val275Ile	missense	Exon 7 of 7	NP_001352688.1
	ICOSLG	NM_001283052.2		c.649G>A	p.Val217Ile	missense	Exon 7 of 7	NP_001269981.1	B7Z1W8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.904G>A	p.Val302Ile	missense	Exon 7 of 7	ENSP00000384432.3	O75144-1
	ICOSLG	ENST00000400379.8	TSL:1	c.*491G>A		3_prime_UTR	Exon 6 of 6	ENSP00000383230.3	K4DIA0
	ICOSLG	ENST00000344330.9	TSL:1	c.898+1015G>A		intron	N/A	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes AF: 0.0000557 AC: 2 AN: 35902 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000994

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248186 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000130 AC: 5 AN: 383512 Hom.: 2 Cov.: 4 AF XY: 0.0000150 AC XY: 3 AN XY: 200074

African (AFR) AF: 0.00 AC: 0 AN: 6620

American (AMR) AF: 0.00 AC: 0 AN: 14650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10916

East Asian (EAS) AF: 0.00 AC: 0 AN: 19176

South Asian (SAS) AF: 0.00 AC: 0 AN: 28356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2808

European-Non Finnish (NFE) AF: 0.0000190 AC: 5 AN: 262634

Other (OTH) AF: 0.00 AC: 0 AN: 19508

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000557 AC: 2 AN: 35902 Hom.: 1 Cov.: 0 AF XY: 0.000120 AC XY: 2 AN XY: 16708

African (AFR) AF: 0.00 AC: 0 AN: 5658

American (AMR) AF: 0.00 AC: 0 AN: 3622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1192

East Asian (EAS) AF: 0.00 AC: 0 AN: 1954

South Asian (SAS) AF: 0.00 AC: 0 AN: 836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 140

European-Non Finnish (NFE) AF: 0.0000994 AC: 2 AN: 20112

Other (OTH) AF: 0.00 AC: 0 AN: 508

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.8
DANN	Benign	0.64
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.77
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.052
Sift	Benign	0.43	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.90	P
Vest4		0.098
MutPred		0.30		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.17
MPC		0.36
ClinPred		0.073	T
GERP RS		1.5
Varity_R		0.047
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs780312517; hg19: chr21-45648922;