Genetic Variant ICOSLG:p.Phe341Ile (chr21-44229931-A-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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. 13/17 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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.56

Publications

1 publications found

Variant links:

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

ICOSLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 1879545.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 60 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ICOSLG	NM_015259.6	MANE Select	c.898+123T>A	intron	N/A	NP_056074.1	O75144-1
ICOSLG	NM_001283050.2		c.898+123T>A	intron	N/A	NP_001269979.1	O75144-2
ICOSLG	NM_001395918.1		c.898+123T>A	intron	N/A	NP_001382847.1	A0A8V8TQV9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ICOSLG	ENST00000400379.8	TSL:1	c.1021T>A	p.Phe341Ile	missense	Exon 6 of 6	ENSP00000383230.3	K4DIA0
ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.898+123T>A		intron	N/A	ENSP00000384432.3	O75144-1
ICOSLG	ENST00000344330.9	TSL:1	c.898+123T>A		intron	N/A	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

157

AN:

77076

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00107

AC:

167

AN:

156024

AF XY:

0.00127

show subpopulations

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 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.:

AF XY:

0.00288

AC XY:

1063

AN XY:

368880

show subpopulations

African (AFR)

AF:

0.0000960

AC:

AN:

20828

American (AMR)

AF:

0.000533

AC:

AN:

18752

Ashkenazi Jewish (ASJ)

AF:

0.00679

AC:

100

AN:

14734

East Asian (EAS)

AF:

0.00

AC:

AN:

23226

South Asian (SAS)

AF:

0.00524

AC:

266

AN:

50742

European-Finnish (FIN)

AF:

0.000679

AC:

AN:

22106

Middle Eastern (MID)

AF:

0.00651

AC:

AN:

3838

European-Non Finnish (NFE)

AF:

0.00251

AC:

1390

AN:

553024

Other (OTH)

AF:

0.00289

AC:

AN:

33212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00204

AC:

157

AN:

77144

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

AN XY:

37450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21860

American (AMR)

AF:

0.00142

AC:

AN:

7726

Ashkenazi Jewish (ASJ)

AF:

0.00868

AC:

AN:

1958

East Asian (EAS)

AF:

0.000306

AC:

AN:

3270

South Asian (SAS)

AF:

0.00231

AC:

AN:

2602

European-Finnish (FIN)

AF:

0.000931

AC:

AN:

4296

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.00341

AC:

115

AN:

33730

Other (OTH)

AF:

0.00183

AC:

AN:

1094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.547

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

Hom.:

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.000899

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.0

(source)

DANN

Benign

0.84

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.23

M_CAP

Benign

0.00048

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.96

PhyloP100

-1.6

PROVEAN

Benign

0.22

REVEL

Benign

0.015

Sift

Uncertain

0.011

Sift4G

Benign

0.29

Vest4

0.16

MVP

0.055

ClinPred

0.0091

GERP RS

-2.5

PromoterAI

-0.0093

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over