21-44230041-AC-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Strong BP6_Very_Strong

The ENST00000400379.8(ICOSLG):c.910del(p.Val304TrpfsTer250) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 9)
  • Exomes 𝑓: 0.00025 (29 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOSLG ENST00000400379.8 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.77

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 -4 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 0.36 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 21-44230041-AC-A is Benign according to our data. Variant chr21-44230041-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 1104881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICOSLG	NM_015259.6	c.898+12del		intron_variant		ENST00000407780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOSLG	ENST00000407780.8	c.898+12del		intron_variant		1	NM_015259.6	A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 76076 Hom.: 0 Cov.: 9 FAILED QC

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: 0.0000306

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000738 AC: 116 AN: 157126 Hom.: 0 AF XY: 0.000672 AC XY: 56 AN XY: 83338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000281

Gnomad ASJ exome AF: 0.000237

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000220

Gnomad FIN exome AF: 0.0000653

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.000685

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000248 AC: 181 AN: 729476 Hom.: 29 Cov.: 9 AF XY: 0.000250 AC XY: 91 AN XY: 364002

Gnomad4 AFR exome AF: 0.0000960

Gnomad4 AMR exome AF: 0.000110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000234

Gnomad4 FIN exome AF: 0.000198

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.000510

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000131 AC: 1 AN: 76126 Hom.: 0 Cov.: 9 AF XY: 0.0000271 AC XY: 1 AN XY: 36886

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000306

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000632 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ICOSLG: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

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: rs753701173; hg19: chr21-45649924;