chrX-71107603-C-T

Variant names:

• chrX-71107603-C-T
• rs560555283
• NM_000206.3:c.*133G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000206.3(IL2RG):​c.*133G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000542 in 387,749 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000062 (0 hom. 9 hem.)
• Consequence: IL2RG NM_000206.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.324
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000356 (4/112245) while in subpopulation SAS AF = 0.00111 (3/2703). AF 95% confidence interval is 0.000302. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 3 XL,AR gene

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.*133G>A		3_prime_UTR	Exon 8 of 8	NP_000197.1	P31785-1
	IL2RG	NM_001438870.1		c.*363G>A		3_prime_UTR	Exon 7 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.*133G>A		3_prime_UTR	Exon 8 of 8	ENSP00000363318.3	P31785-1
	ENSG00000285171	ENST00000646505.1		n.924+674G>A		intron	N/A	ENSP00000496673.1	A0A2R8YE73
	IL2RG	ENST00000276110.6	TSL:2	n.1836G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 112192 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000617 AC: 17 AN: 275504 Hom.: 0 Cov.: 5 AF XY: 0.000115 AC XY: 9 AN XY: 78446

African (AFR) AF: 0.00 AC: 0 AN: 7698

American (AMR) AF: 0.00 AC: 0 AN: 7985

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7792

East Asian (EAS) AF: 0.00 AC: 0 AN: 18978

South Asian (SAS) AF: 0.00200 AC: 15 AN: 7482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1107

European-Non Finnish (NFE) AF: 0.00000559 AC: 1 AN: 178983

Other (OTH) AF: 0.0000625 AC: 1 AN: 15997

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112245 Hom.: 0 Cov.: 23 AF XY: 0.0000872 AC XY: 3 AN XY: 34421

African (AFR) AF: 0.0000323 AC: 1 AN: 30956

American (AMR) AF: 0.00 AC: 0 AN: 10671

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00111 AC: 3 AN: 2703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53141

Other (OTH) AF: 0.00 AC: 0 AN: 1522

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.74
DANN	Benign	0.64
PhyloP100		-0.32

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

Other links and lift over

dbSNP: rs560555283; hg19: chrX-70327453;