chr5-35871109-G-C

Variant names:

• chr5-35871109-G-C
• rs201790329
• NM_002185.5:c.433G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002185.5(IL7R):​c.433G>C​(p.Asp145His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D145N) 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: 5.70
• 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: 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.433G>C	p.Asp145His	missense	Exon 4 of 8	NP_002176.2
	IL7R	NM_001437964.1		c.433G>C	p.Asp145His	missense	Exon 4 of 7	NP_001424893.1
	IL7R	NM_001410734.1		c.433G>C	p.Asp145His	missense	Exon 4 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.433G>C	p.Asp145His	missense	Exon 4 of 8	ENSP00000306157.3	P16871-1
	IL7R	ENST00000877114.1		c.433G>C	p.Asp145His	missense	Exon 4 of 7	ENSP00000547173.1
	IL7R	ENST00000506850.5	TSL:2	c.433G>C	p.Asp145His	missense	Exon 4 of 6	ENSP00000421207.1	P16871-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.25
Sift	Benign	0.20	T
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.70		Loss of stability (P = 0.1013)
MVP		0.92
MPC		0.10
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.48
Mutation Taster		=24/76	disease causing

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: rs201790329; hg19: chr5-35871211;