14-23375743-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022789.4(IL25):c.397C>G(p.Leu133Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: IL25 NM_022789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

Genes affected

IL25 (HGNC:13765): (interleukin 25) The protein encoded by this gene is a cytokine that shares sequence similarity with interleukin 17. This cytokine can induce NF-kappaB activation, and stimulate the production of interleukin 8. Both this cytokine and interleukin 17B are ligands for the cytokine receptor IL17BR. Studies of a similar gene in mice suggest that this cytokine may be a pro-inflammatory cytokine favoring the Th2-type immune response. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33286896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL25	NM_172314.2	c.349C>G	p.Leu117Val	missense_variant	3/3	ENST00000397242.3
IL25	NM_022789.4	c.397C>G	p.Leu133Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL25	ENST00000397242.3	c.349C>G	p.Leu117Val	missense_variant	3/3	1	NM_172314.2	P2
IL25	ENST00000329715.2	c.397C>G	p.Leu133Val	missense_variant	2/2	1		A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

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

Oct 03, 2022

The c.397C>G (p.L133V) alteration is located in exon 2 (coding exon 2) of the IL25 gene. This alteration results from a C to G substitution at nucleotide position 397, causing the leucine (L) at amino acid position 133 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	0.30
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.64	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.18
Sift	Benign	0.17	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.22
MutPred		0.48		.;Gain of sheet (P = 0.1539);
MVP		0.61
MPC		0.29
ClinPred		0.85	D
GERP RS		4.5
Varity_R		0.16
gMVP		0.21

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: rs914496697; hg19: chr14-23844952;