21-44229040-G-A

Variant names:

• chr21-44229040-G-A
• rs1162453616
• NM_015259.6:c.903C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_015259.6(ICOSLG):​c.903C>T​(p.His301His) variant causes a synonymous 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOSLG NM_015259.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.53
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 21-44229040-G-A is Benign according to our data. Variant chr21-44229040-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2973346.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015259.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	NM_015259.6	MANE Select	c.903C>T	p.His301His	synonymous	Exon 7 of 7	NP_056074.1	O75144-1
	ICOSLG	NM_001365759.2		c.822C>T	p.His274His	synonymous	Exon 7 of 7	NP_001352688.1
	ICOSLG	NM_001283052.2		c.648C>T	p.His216His	synonymous	Exon 7 of 7	NP_001269981.1	B7Z1W8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.903C>T	p.His301His	synonymous	Exon 7 of 7	ENSP00000384432.3	O75144-1
	ICOSLG	ENST00000400379.8	TSL:1	c.*490C>T		3_prime_UTR	Exon 6 of 6	ENSP00000383230.3	K4DIA0
	ICOSLG	ENST00000344330.9	TSL:1	c.898+1014C>T		intron	N/A	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248172 AF XY: 0.00

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000256 AC: 1 AN: 390862 Hom.: 0 Cov.: 4 AF XY: 0.00000491 AC XY: 1 AN XY: 203624

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000150 AC: 1 AN: 6662

American (AMR) AF: 0.00 AC: 0 AN: 14766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11000

East Asian (EAS) AF: 0.00 AC: 0 AN: 19252

South Asian (SAS) AF: 0.00 AC: 0 AN: 28486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2820

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 269182

Other (OTH) AF: 0.00 AC: 0 AN: 19804

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1162453616; hg19: chr21-45648923;