8-78733733-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000880.4(IL7):c.514A>G(p.Met172Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,448,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: IL7 NM_000880.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

Genes affected

IL7 (HGNC:6023): (interleukin 7) The protein encoded by this gene is a cytokine important for B and T cell development. This cytokine and the hepatocyte growth factor (HGF) form a heterodimer that functions as a pre-pro-B cell growth-stimulating factor. IL7 is found to be a cofactor for V(D)J rearrangement of the T cell receptor beta (TCRB) during early T cell development. This cytokine can be produced locally by intestinal epithelial and epithelial goblet cells, and may serve as a regulatory factor for intestinal mucosal lymphocytes. IL7 plays an essential role in lymphoid cell survival, and in the maintenance of naive and memory T cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their presence in normal tissues has not been confirmed. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can be a potent inducer of proinflammatory cytokines and chemokines which may defend against the infection, but may also mediate destructive lung injury. Elevated serum IL7 levels, together with several other circulating cytokines and chemokines, has been found to be associated with the severity of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09525797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL7	NM_000880.4	c.514A>G	p.Met172Val	missense_variant	6/6	ENST00000263851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL7	ENST00000263851.9	c.514A>G	p.Met172Val	missense_variant	6/6	1	NM_000880.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000631 AC: 15 AN: 237680 Hom.: 0 AF XY: 0.0000545 AC XY: 7 AN XY: 128426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000318 AC: 46 AN: 1448420 Hom.: 0 Cov.: 29 AF XY: 0.0000278 AC XY: 20 AN XY: 719998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000397

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.514A>G (p.M172V) alteration is located in exon 6 (coding exon 6) of the IL7 gene. This alteration results from a A to G substitution at nucleotide position 514, causing the methionine (M) at amino acid position 172 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.36	T;T;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.7	N;.;.;N
REVEL	Benign	0.047
Sift	Benign	0.041	D;.;.;D
Sift4G	Uncertain	0.037	D;D;T;D
Polyphen		0.0010	B;.;.;.
Vest4		0.080
MutPred		0.33		Gain of ubiquitination at K169 (P = 0.0726);.;.;.;
MVP		0.12
MPC		0.17
ClinPred		0.051	T
GERP RS		3.8
Varity_R		0.31
gMVP		0.073

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

Publications

LitVar

Other links and lift over

dbSNP: rs752005617; hg19: chr8-79645968;