19-49889981-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152899.2(IL4I1):c.1393G>A(p.Glu465Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000448 in 1,570,124 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: IL4I1 NM_152899.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.249

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028167963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4I1	NM_152899.2	c.1393G>A	p.Glu465Lys	missense_variant	8/8	ENST00000391826.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4I1	ENST00000391826.7	c.1393G>A	p.Glu465Lys	missense_variant	8/8	1	NM_152899.2	P2
IL4I1	ENST00000341114.7	c.1459G>A	p.Glu487Lys	missense_variant	10/10	1		A2
IL4I1	ENST00000595948.5	c.1459G>A	p.Glu487Lys	missense_variant	10/10	1		A2
IL4I1	ENST00000601717.5	c.*1245G>A		3_prime_UTR_variant, NMD_transcript_variant	11/11	1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000396 AC: 69 AN: 174168 Hom.: 0 AF XY: 0.000468 AC XY: 44 AN XY: 94060

Gnomad AFR exome AF: 0.000106

Gnomad AMR exome AF: 0.000225

Gnomad ASJ exome AF: 0.000805

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000615

Gnomad NFE exome AF: 0.000719

Gnomad OTH exome AF: 0.000638

GnomAD4 exome AF: 0.000457 AC: 648 AN: 1417766 Hom.: 1 Cov.: 32 AF XY: 0.000442 AC XY: 310 AN XY: 701754

Gnomad4 AFR exome AF: 0.0000621

Gnomad4 AMR exome AF: 0.000131

Gnomad4 ASJ exome AF: 0.000827

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000101

Gnomad4 NFE exome AF: 0.000541

Gnomad4 OTH exome AF: 0.000341

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74502

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000456 Hom.: 0

Bravo AF: 0.000340

ExAC AF: 0.000332 AC: 39

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

Dec 05, 2022

The c.1459G>A (p.E487K) 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 1459, causing the glutamic acid (E) at amino acid position 487 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	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	10
Dann	Benign	0.97
DEOGEN2	Uncertain	0.49	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.70	T;.;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	N;N;.
REVEL	Benign	0.19
Sift	Benign	0.41	T;T;.
Sift4G	Benign	0.36	T;T;T
Polyphen		0.050	B;B;B
Vest4		0.073
MVP		0.46
MPC		1.2
ClinPred		0.015	T
GERP RS		-1.3
Varity_R		0.13
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

LitVar

Other links and lift over

dbSNP: rs541635369; hg19: chr19-50393238; COSMIC: COSV55579853; COSMIC: COSV55579853;