19-49890266-C-T

Variant summary

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

The NM_152899.2(IL4I1):c.1108G>A(p.Glu370Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,432,844 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IL4I1 NM_152899.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0970

Genes affected

IL4I1 (HGNC:19094): (interleukin 4 induced 1) This gene encodes a secreted L-amino acid oxidase protein which primarily catabolizes L-phenylalanine and, to a lesser extent, L-arginine. The expression of this gene is induced by the cytokine interleukin 4 in B cells. This gene is also expressed in macrophages and dendritic cells. This protein may play a role immune system escape as it is expressed in tumor-associated macrophages and suppresses T-cell responses. This protein also contains domains thought to be involved in the binding of flavin adenine dinucleotide (FAD) cofactor. Multiple transcript variants encoding different isoforms have been found for this gene. Some transcripts of this gene share a promoter and exons of the 5' UTR with the overlapping NUP62 gene. [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=0.11940664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4I1	NM_152899.2	c.1108G>A	p.Glu370Lys	missense_variant	8/8	ENST00000391826.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4I1	ENST00000391826.7	c.1108G>A	p.Glu370Lys	missense_variant	8/8	1	NM_152899.2	P2
IL4I1	ENST00000341114.7	c.1174G>A	p.Glu392Lys	missense_variant	10/10	1		A2
IL4I1	ENST00000595948.5	c.1174G>A	p.Glu392Lys	missense_variant	10/10	1		A2
IL4I1	ENST00000601717.5	c.*960G>A		3_prime_UTR_variant, NMD_transcript_variant	11/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1432844 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 710682

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: 0.00000182

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

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 27, 2022

The c.1174G>A (p.E392K) alteration is located in exon 10 (coding exon 7) of the IL4I1 gene. This alteration results from a G to A substitution at nucleotide position 1174, causing the glutamic acid (E) at amino acid position 392 to be replaced by a lysine (K). 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	0.099
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	12
Dann	Benign	0.91
DEOGEN2	Benign	0.39	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.81	T;.;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.98	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.060	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.92	T;T;.
Sift4G	Benign	0.48	T;T;T
Polyphen		0.029	B;B;B
Vest4		0.089
MutPred		0.62		Gain of MoRF binding (P = 0.0122);.;.;
MVP		0.20
MPC		1.2
ClinPred		0.071	T
GERP RS		-3.4
Varity_R		0.075
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50393523;