rs587778405

Variant names:

• chr5-35873604-G-T
• rs587778405
• NM_002185.5:c.662G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-35873604-G-T
• chr5-35873604-G-A

Variant summary

Our verdict is Pathogenic. The variant received 4 ACMG points: 4P and 0B. PM3 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The c.662G>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Serine by Isoleucine at amino acid 221 (p.Ser221Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PMID 17201233: Twin B was diagnosed with SCID and was homozygous for this variant. A fraternal twin A with SCID was also reported, but the genotype of this twin was not reported.PMID 18641513: Three individuals were diagnosed with SCID and were homozygous for this variant.This variant has been detected in 7 individuals with SCID. Four individuals were homozygous for the variant (1pt maximum, PMIDs 17201233, 18641513). Two individuals recorded in the Invitae internal database were heterozygous for this variant and a c.83-2A>T variant. The c.83-2A>T variant is classified as pathogenic following the SCID-VCEP specification. The trans phase was confirmed in one patient but not the other (1.5pt in total). One individual, also from Invitae internal database, was heterozygous for this variant and a c.707-2A>G variant. The c.707-2A>G variant is classified as a pathogenic variant following the SCID-VCEP specification. The trans phase was not confirmed in this patient (0.5pt). 4pt in total, PM3_very strong is met.The individual with this variant and c.707-2A>G variant showed a T-B+NK+ lymphocyte profile, and abnormal newborn TREC result, and a diagnosis of SCID. A comprehensive SCID and CID panel did not identify an alternative cause of the disease. 1.25pt for PP4 and PP4 is met (PP4). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3_Very strong, PP4. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160099/MONDO:0012163/119

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IL7R NM_002185.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 5.76
• Publications: 2 publications found

Genes affected

IL7R (HGNC:6024): (interleukin 7 receptor) The protein encoded by this gene is a receptor for interleukin 7 (IL7). The function of this receptor requires the interleukin 2 receptor, gamma chain (IL2RG), which is a common gamma chain shared by the receptors of various cytokines, including interleukins 2, 4, 7, 9, and 15. This protein has been shown to play a critical role in V(D)J recombination during lymphocyte development. Defects in this gene may be associated with severe combined immunodeficiency (SCID). Alternatively spliced transcript variants have been found. [provided by RefSeq, Dec 2015]

IL7R Gene-Disease associations (from GenCC):

• immunodeficiency 104

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for IL7R are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002185.5. 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
	IL7R	NM_002185.5	MANE Select	c.662G>T	p.Ser221Ile	missense	Exon 5 of 8	NP_002176.2
	IL7R	NM_001437964.1		c.662G>T	p.Ser221Ile	missense	Exon 5 of 7	NP_001424893.1
	IL7R	NM_001410734.1		c.662G>T	p.Ser221Ile	missense	Exon 5 of 7	NP_001397663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL7R	ENST00000303115.8	TSL:1 MANE Select	c.662G>T	p.Ser221Ile	missense	Exon 5 of 8	ENSP00000306157.3	P16871-1
	IL7R	ENST00000877114.1		c.662G>T	p.Ser221Ile	missense	Exon 5 of 7	ENSP00000547173.1
	IL7R	ENST00000506850.5	TSL:2	c.662G>T	p.Ser221Ile	missense	Exon 5 of 6	ENSP00000421207.1	P16871-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461644 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111812

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000293 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Immunodeficiency 104 (2)
1	-	-	not provided (1)
1	-	-	Severe combined immunodeficiency disease (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.8
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.84		Gain of catalytic residue at S221 (P = 0.0674)
MVP		0.98
MPC		0.11
ClinPred		1.0	D
GERP RS		6.0
PromoterAI		0.0016	Neutral
Varity_R		0.93
gMVP		0.83
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs587778405; hg19: chr5-35873706;