21-44229035-C-G

Position:

• chr21-44229035-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_015259.6(ICOSLG):​c.908G>C​(p.Ter303SerextTer59) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: ICOSLG NM_015259.6 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

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 Uncertain_significance. Variant got 2 ACMG points.

• PM4: Stoplost variant in NM_015259.6 Downstream stopcodon found after 16 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICOSLG	NM_015259.6	c.908G>C	p.Ter303SerextTer59	stop_lost	7/7	ENST00000407780.8	NP_056074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICOSLG	ENST00000407780.8	c.908G>C	p.Ter303SerextTer59	stop_lost	7/7	1	NM_015259.6	ENSP00000384432	A2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000725 AC: 18 AN: 248140 Hom.: 0 AF XY: 0.0000964 AC XY: 13 AN XY: 134918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 4

GnomAD4 genome Cov.: 0

ExAC AF: 0.0000661 AC: 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

Nov 28, 2023

This sequence change disrupts the translational stop signal of the ICOSLG mRNA. It is expected to extend the length of the ICOSLG protein by 59 additional amino acid residues. This variant is present in population databases (rs746057000, gnomAD 0.05%). 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: 1392572). 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
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.2
DANN	Benign	0.76
Eigen	Uncertain	0.34
Eigen_PC	Benign	-0.048
FATHMM_MKL	Benign	0.27	N
MutationTaster	Benign	1.0	N;N;N;N
Vest4		0.093
GERP RS		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs746057000; hg19: chr21-45648918; COSMIC: COSV60265489;