chr21-44230087-C-T

Position:

• chr21-44230087-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000407780.8(ICOSLG):​c.865G>A​(p.Ala289Thr) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A289V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 8)
• Consequence: ICOSLG ENST00000407780.8 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.151

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04897961).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICOSLG	NM_015259.6	c.865G>A	p.Ala289Thr	missense_variant, splice_region_variant	6/7	ENST00000407780.8	NP_056074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICOSLG	ENST00000407780.8	c.865G>A	p.Ala289Thr	missense_variant, splice_region_variant	6/7	1	NM_015259.6	ENSP00000384432.3

Frequencies

GnomAD3 genomes Cov.: 8

GnomAD3 exomes AF: 0.00000684 AC: 1 AN: 146262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 77262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 5

GnomAD4 genome Cov.: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 289 of the ICOSLG protein (p.Ala289Thr). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ICOSLG-related conditions. 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 threonine 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.79
DEOGEN2	Benign	0.091	.;T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.91	N;N;N;N
REVEL	Benign	0.029
Sift	Benign	0.33	T;T;D;D
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.36	.;B;.;.
Vest4		0.075
MutPred		0.31		Loss of catalytic residue at A289 (P = 0.0024);Loss of catalytic residue at A289 (P = 0.0024);Loss of catalytic residue at A289 (P = 0.0024);.;
MVP		0.14
MPC		0.55
ClinPred		0.13	T
GERP RS		1.8
Varity_R		0.050
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs1313892790; hg19: chr21-45649970; COSMIC: COSV100723938;