14-23373210-A-C

Variant summary

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

The NM_022789.4(IL25):c.92A>C(p.His31Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 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: 0.0000014 (0 hom.)
• Consequence: IL25 NM_022789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19459304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL25	NM_172314.2	c.44A>C	p.His15Pro	missense_variant	2/3	ENST00000397242.3
IL25	NM_022789.4	c.92A>C	p.His31Pro	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL25	ENST00000397242.3	c.44A>C	p.His15Pro	missense_variant	2/3	1	NM_172314.2	P2
IL25	ENST00000329715.2	c.92A>C	p.His31Pro	missense_variant	1/2	1		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251372 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 05, 2023

The c.92A>C (p.H31P) alteration is located in exon 1 (coding exon 1) of the IL25 gene. This alteration results from a A to C substitution at nucleotide position 92, causing the histidine (H) at amino acid position 31 to be replaced by a proline (P). 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	0.093
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.075
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.0010	B;B
Vest4		0.53
MutPred		0.58		.;Loss of catalytic residue at H31 (P = 0.0064);
MVP		0.61
MPC		0.14
ClinPred		0.34	T
GERP RS		3.0
Varity_R		0.38
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1566496988; hg19: chr14-23842419;