5-35857003-G-A

Variant names:

• chr5-35857003-G-A
• rs776642878
• NM_002185.5:c.26G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002185.5(IL7R):​c.26G>A​(p.Gly9Asp) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL7R NM_002185.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849
• Publications: 5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33240426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL7R	NM_002185.5	c.26G>A	p.Gly9Asp	missense_variant	Exon 1 of 8	ENST00000303115.8	NP_002176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8	c.26G>A	p.Gly9Asp	missense_variant	Exon 1 of 8	1	NM_002185.5	ENSP00000306157.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.4	.;.;M;M;.
PhyloP100		0.85
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.9	D;D;N;N;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;T;D;D
Polyphen		0.98	.;.;D;.;.
Vest4		0.85, 0.84, 0.73
MutPred		0.34		Loss of catalytic residue at S13 (P = 0.1139);Loss of catalytic residue at S13 (P = 0.1139);Loss of catalytic residue at S13 (P = 0.1139);Loss of catalytic residue at S13 (P = 0.1139);Loss of catalytic residue at S13 (P = 0.1139);
MVP		0.92
MPC		0.10
ClinPred		0.94	D
GERP RS		2.5
PromoterAI		-0.026	Neutral
Varity_R		0.14
gMVP		0.65
Mutation Taster		=85/15	polymorphism

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: rs776642878; hg19: chr5-35857105;