21-44229931-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000400379.8(ICOSLG):c.1021T>A(p.Phe341Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (60 hom., cov: 10)
  • Exomes 𝑓: 0.0026 (755 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOSLG ENST00000400379.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.56

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043032765).
• BP6: Variant 21-44229931-A-T is Benign according to our data. Variant chr21-44229931-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1879545.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICOSLG	NM_015259.6	c.898+123T>A		intron_variant		ENST00000407780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOSLG	ENST00000407780.8	c.898+123T>A		intron_variant		1	NM_015259.6	A2

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 157 AN: 77076 Hom.: 60 Cov.: 10

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00143

Gnomad ASJ AF: 0.00868

Gnomad EAS AF: 0.000305

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.000931

Gnomad MID AF: 0.00446

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00185

GnomAD3 exomes AF: 0.00107 AC: 167 AN: 156024 Hom.: 1 AF XY: 0.00127 AC XY: 105 AN XY: 82798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00137

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00257 AC: 1904 AN: 740462 Hom.: 755 Cov.: 12 AF XY: 0.00288 AC XY: 1063 AN XY: 368880

Gnomad4 AFR exome AF: 0.0000960

Gnomad4 AMR exome AF: 0.000533

Gnomad4 ASJ exome AF: 0.00679

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00524

Gnomad4 FIN exome AF: 0.000679

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00289

GnomAD4 genome AF: 0.00204 AC: 157 AN: 77144 Hom.: 60 Cov.: 10 AF XY: 0.00179 AC XY: 67 AN XY: 37450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00142

Gnomad4 ASJ AF: 0.00868

Gnomad4 EAS AF: 0.000306

Gnomad4 SAS AF: 0.00231

Gnomad4 FIN AF: 0.000931

Gnomad4 NFE AF: 0.00341

Gnomad4 OTH AF: 0.00183

Alfa AF: 0.00110 Hom.: 3

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.000899 AC: 35

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

Nov 01, 2022

ICOSLG: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.0
Dann	Benign	0.84
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.00048	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	0.22	N
REVEL	Benign	0.015
Sift	Uncertain	0.011	D
Sift4G	Benign	0.29	T
Vest4		0.16
MVP		0.055
ClinPred		0.0091	T
GERP RS		-2.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200250197; hg19: chr21-45649814;