21-44230086-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_015259.6(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 NM_015259.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.509

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 -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: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICOSLG	NM_015259.6	c.866C>T	p.Ala289Val	missense_variant	6/7	ENST00000407780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOSLG	ENST00000407780.8	c.866C>T	p.Ala289Val	missense_variant	6/7	1	NM_015259.6	A2

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 29 AN: 73632 Hom.: 9 Cov.: 9

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: 56 AN: 146326 Hom.: 0 AF XY: 0.000272 AC XY: 21 AN XY: 77290

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.: 6 AF XY: 0.000563 AC XY: 189 AN XY: 335570

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: 30 AN: 73688 Hom.: 9 Cov.: 9 AF XY: 0.000531 AC XY: 19 AN XY: 35772

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.: 2

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000736 AC: 6

ExAC AF: 0.000130 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	7.5
Dann	Benign	0.18
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.42	N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
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	T
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

Other links and lift over

dbSNP: rs199878735; hg19: chr21-45649969;