Genetic Variant ICOSLG:p.Arg374Gln (chr21-44229831-C-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.1121G>A(p.Arg374Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000426 in 1,079,362 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 3 hom., cov: 11)

Exomes 𝑓: 0.000037 ( 10 hom. )

Consequence

ICOSLG
ENST00000400379.8 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.03

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=0.0036784112).

BP6

Variant 21-44229831-C-T is Benign according to our data. Variant chr21-44229831-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2652737.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 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+223G>A	intron	N/A	NP_056074.1	O75144-1
ICOSLG	NM_001283050.2		c.898+223G>A	intron	N/A	NP_001269979.1	O75144-2
ICOSLG	NM_001395918.1		c.898+223G>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.1121G>A	p.Arg374Gln	missense	Exon 6 of 6	ENSP00000383230.3	K4DIA0
ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.898+223G>A		intron	N/A	ENSP00000384432.3	O75144-1
ICOSLG	ENST00000344330.9	TSL:1	c.898+223G>A		intron	N/A	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes

AF:

0.000110

AC:

AN:

81994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00101

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

GnomAD2 exomes

AF:

0.00951

AC:

1414

AN:

148714

AF XY:

0.00897

show subpopulations

Gnomad AFR exome

AF:

0.00321

Gnomad AMR exome

AF:

0.00403

Gnomad ASJ exome

AF:

0.00720

Gnomad EAS exome

AF:

0.0000925

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.0000371

AC:

AN:

997368

Hom.:

Cov.:

AF XY:

0.0000243

AC XY:

AN XY:

494812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28990

American (AMR)

AF:

0.000666

AC:

AN:

24030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18372

East Asian (EAS)

AF:

0.00

AC:

AN:

33646

South Asian (SAS)

AF:

0.00

AC:

AN:

62478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31104

Middle Eastern (MID)

AF:

0.000457

AC:

AN:

4374

European-Non Finnish (NFE)

AF:

0.0000240

AC:

AN:

750650

Other (OTH)

AF:

0.0000229

AC:

AN:

43724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000110

AC:

AN:

81994

Hom.:

Cov.:

AF XY:

0.0000505

AC XY:

AN XY:

39620

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23674

American (AMR)

AF:

0.00101

AC:

AN:

7904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2036

East Asian (EAS)

AF:

0.00

AC:

AN:

3648

South Asian (SAS)

AF:

0.00

AC:

AN:

2428

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4642

Middle Eastern (MID)

AF:

0.00

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

35846

Other (OTH)

AF:

0.000862

AC:

AN:

1160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0114

Hom.:

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0189

AC:

ExAC

AF:

0.00723

AC:

185

Asia WGS

AF:

0.000289

AC:

AN:

3476

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

Benign

0.12

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.34

(source)

DANN

Benign

0.81

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0090

LIST_S2

Benign

0.34

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.99

PhyloP100

-3.0

PROVEAN

Benign

-0.050

REVEL

Benign

0.013

Sift

Pathogenic

0.0

Vest4

0.12

MVP

0.085

ClinPred

0.0036

GERP RS

-2.7

PromoterAI

-0.028

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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