chr14-23375635-G-T

Position:

• chr14-23375635-G-T

Variant summary

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

The NM_022789.4(IL25):​c.289G>T​(p.Asp97Tyr) 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: IL25 NM_022789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68

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 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, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL25	NM_172314.2	c.241G>T	p.Asp81Tyr	missense_variant	3/3	ENST00000397242.3	NP_758525.1
IL25	NM_022789.4	c.289G>T	p.Asp97Tyr	missense_variant	2/2		NP_073626.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL25	ENST00000397242.3	c.241G>T	p.Asp81Tyr	missense_variant	3/3	1	NM_172314.2	ENSP00000380417	P2
IL25	ENST00000329715.2	c.289G>T	p.Asp97Tyr	missense_variant	2/2	1		ENSP00000328111	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Oct 17, 2023

The c.289G>T (p.D97Y) alteration is located in exon 2 (coding exon 2) of the IL25 gene. This alteration results from a G to T substitution at nucleotide position 289, causing the aspartic acid (D) at amino acid position 97 to be replaced by a tyrosine (Y). 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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Pathogenic	3.1	.;M
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.0	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.85		.;Loss of disorder (P = 0.0329);
MVP		0.86
MPC		0.52
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.92
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr14-23844844; COSMIC: COSV59306920; COSMIC: COSV59306920;