X-71110292-A-T

Variant names:

• chrX-71110292-A-T
• rs111033621
• NM_000206.3:c.458T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000206.3(IL2RG):​c.458T>A​(p.Ile153Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I153T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.53
• Publications: 3 publications found

Genes affected

IL2RG (HGNC:6010): (interleukin 2 receptor subunit gamma) The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder. [provided by RefSeq, Mar 2010]

IL2RG Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to gamma chain deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000206.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71110292-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 870713.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant X-71110292-A-T is Pathogenic according to our data. Variant chrX-71110292-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10022.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000206.3. 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
	IL2RG	NM_000206.3	MANE Select	c.458T>A	p.Ile153Asn	missense	Exon 4 of 8	NP_000197.1
	IL2RG	NM_001438870.1		c.458T>A	p.Ile153Asn	missense	Exon 4 of 7	NP_001425799.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.458T>A	p.Ile153Asn	missense	Exon 4 of 8	ENSP00000363318.3
	ENSG00000285171	ENST00000646505.1		n.458T>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000496673.1
	IL2RG	ENST00000482750.6	TSL:5	c.458T>A	p.Ile153Asn	missense	Exon 4 of 7	ENSP00000421262.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked severe combined immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.64
Sift	Benign	0.15	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.85		Gain of disorder (P = 0.0212)
MVP		0.98
MPC		2.1
ClinPred		0.94	D
GERP RS		5.3
PromoterAI		-0.021	Neutral
Varity_R		0.86
gMVP		0.90
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs111033621; hg19: chrX-70330142;