chr21-44230086-G-A

Position:

chr21-44230086-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000407780.8(ICOSLG):c.866C>T(p.Ala289Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A289T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 9 hom., cov: 9)

Exomes 𝑓: 0.00057 ( 142 hom. )

Failed GnomAD Quality Control

Consequence

ICOSLG
ENST00000407780.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.509

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010702461).

BP6

Variant 21-44230086-G-A is Benign according to our data. Variant chr21-44230086-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1372557.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICOSLG	NM_015259.6 linkuse as main transcript	c.866C>T	p.Ala289Val	missense_variant	6/7	ENST00000407780.8	NP_056074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICOSLG	ENST00000407780.8 linkuse as main transcript	c.866C>T	p.Ala289Val	missense_variant	6/7	1	NM_015259.6	ENSP00000384432	A2	O75144-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

73632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000517

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000400

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000383

AC:

AN:

146326

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

77290

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000789

Gnomad ASJ exome

AF:

0.000137

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000993

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000485

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000572

AC:

389

AN:

680140

Hom.:

142

Cov.:

AF XY:

0.000563

AC XY:

189

AN XY:

335570

show subpopulations

Gnomad4 AFR exome

AF:

0.000958

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.0000795

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000473

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000494

Gnomad4 OTH exome

AF:

0.00120

GnomAD4 genome

AF:

0.000407

AC:

AN:

73688

Hom.:

Cov.:

AF XY:

0.000531

AC XY:

AN XY:

35772

show subpopulations

Gnomad4 AFR

AF:

0.000244

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000517

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000401

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000521

Hom.:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000736

AC:

ExAC

AF:

0.000130

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 289 of the ICOSLG protein (p.Ala289Val). This variant is present in population databases (rs199878735, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ICOSLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 1372557). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.5

DANN

Benign

0.18

DEOGEN2

Benign

0.085

.;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.64

T;T;T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.42

N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.0080

Sift

Benign

0.41

T;T;T;T

Sift4G

Benign

0.55

T;T;T;T

Polyphen

0.0020

.;B;.;.

Vest4

0.089

MVP

0.076

MPC

0.44

ClinPred

0.033

GERP RS

-0.23

Varity_R

0.028

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over