19-49889885-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152899.2(IL4I1):c.1489G>A(p.Ala497Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IL4I1 NM_152899.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4I1	NM_152899.2	c.1489G>A	p.Ala497Thr	missense_variant	8/8	ENST00000391826.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4I1	ENST00000391826.7	c.1489G>A	p.Ala497Thr	missense_variant	8/8	1	NM_152899.2	P2
IL4I1	ENST00000341114.7	c.1555G>A	p.Ala519Thr	missense_variant	10/10	1		A2
IL4I1	ENST00000595948.5	c.1555G>A	p.Ala519Thr	missense_variant	10/10	1		A2
IL4I1	ENST00000601717.5	c.*1341G>A		3_prime_UTR_variant, NMD_transcript_variant	11/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Aug 17, 2022

The c.1555G>A (p.A519T) 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 1555, causing the alanine (A) at amino acid position 519 to be replaced by a threonine (T). 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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.9	M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0080	D;D;.
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.72
MutPred		0.86		Gain of glycosylation at S496 (P = 0.1087);.;.;
MVP		0.74
MPC		2.1
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.39
gMVP		0.93

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: chr19-50393142;