21-44229832-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PVS1_Strong BP6_Moderate BS2

The ENST00000400379.8(ICOSLG):c.1120C>T(p.Arg374Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (7 hom., cov: 11)
  • Exomes 𝑓: 0.00016 (17 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOSLG ENST00000400379.8 stop_gained
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.982

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.212 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 21-44229832-G-A is Benign according to our data. Variant chr21-44229832-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2652738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICOSLG	NM_015259.6	c.898+222C>T		intron_variant		ENST00000407780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOSLG	ENST00000407780.8	c.898+222C>T		intron_variant		1	NM_015259.6	A2

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 103 AN: 81870 Hom.: 7 Cov.: 11

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000380

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: 0.00

Gnomad OTH AF: 0.000862

GnomAD3 exomes AF: 0.000161 AC: 24 AN: 149202 Hom.: 0 AF XY: 0.000125 AC XY: 10 AN XY: 80214

Gnomad AFR exome AF: 0.00219

Gnomad AMR exome AF: 0.000244

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000157 AC: 156 AN: 995808 Hom.: 17 Cov.: 21 AF XY: 0.000148 AC XY: 73 AN XY: 494086

Gnomad4 AFR exome AF: 0.00384

Gnomad4 AMR exome AF: 0.000541

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000298

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000147

Gnomad4 OTH exome AF: 0.000458

GnomAD4 genome AF: 0.00126 AC: 103 AN: 81938 Hom.: 7 Cov.: 11 AF XY: 0.00139 AC XY: 55 AN XY: 39644

Gnomad4 AFR AF: 0.00418

Gnomad4 AMR AF: 0.000379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000853

Alfa AF: 0.000713 Hom.: 0

ExAC AF: 0.0000388 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

ICOSLG: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.9
Dann	Benign	0.90
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0043	N
MutationTaster	Benign	1.0	D;N;N;N
Vest4		0.12
GERP RS		-1.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs188761017; hg19: chr21-45649715; COSMIC: COSV60267328;