X-71110292-A-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_000206.3(IL2RG):​c.458T>C​(p.Ile153Thr) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I153N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.53

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]

ENSG00000285171 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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-T is described in ClinVar as [Pathogenic]. Clinvar id is 10022.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776
• PP5: Variant X-71110292-A-G is Pathogenic according to our data. Variant chrX-71110292-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 870713.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.458T>C	p.Ile153Thr	missense_variant	Exon 4 of 8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.458T>C	p.Ile153Thr	missense_variant	Exon 4 of 7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.458T>C	p.Ile153Thr	missense_variant	Exon 4 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.458T>C		non_coding_transcript_exon_variant	Exon 4 of 12			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.55	N;N
REVEL	Uncertain	0.64
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;.
Vest4		0.53
MutPred		0.68		Gain of disorder (P = 0.0375);.;
MVP		0.97
MPC		1.7
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.44
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033621; hg19: chrX-70330142;