rs199727195

Variant names:

• chr5-35871136-C-A
• rs199727195
• NM_002185.5:c.460C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-35871136-C-A
• chr5-35871136-C-G
• chr5-35871136-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002185.5(IL7R):​c.460C>A​(p.His154Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H154Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IL7R NM_002185.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL7R	NM_002185.5	c.460C>A	p.His154Asn	missense_variant	Exon 4 of 8	ENST00000303115.8	NP_002176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8	c.460C>A	p.His154Asn	missense_variant	Exon 4 of 8	1	NM_002185.5	ENSP00000306157.3
IL7R	ENST00000506850.5	c.460C>A	p.His154Asn	missense_variant	Exon 4 of 6	2		ENSP00000421207.1
IL7R	ENST00000514217.5	n.460C>A		non_coding_transcript_exon_variant	Exon 4 of 6	2		ENSP00000427688.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		4.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;.
Vest4		0.58
MutPred		0.79		Loss of catalytic residue at Q156 (P = 0.079);Loss of catalytic residue at Q156 (P = 0.079);
MVP		0.92
MPC		0.10
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.34
Mutation Taster		=67/33	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: rs199727195; hg19: chr5-35871238;