Genetic Variant IL36A:p.Leu65Met (chr2-113006666-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014440.3(IL36A):c.193C>A(p.Leu65Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,614,146 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00050 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

IL36A
NM_014440.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.666

Variant links:

Genes affected

IL36A (HGNC:15562): (interleukin 36 alpha) The protein encoded by this gene is a cytokine that can activate NF-kappa-B and MAPK signaling pathways to generate an inflammatory response. The encoded protein functions primarily in skin and demonstrates increased expression in psoriasis. In addition, decreased expression of this gene has been linked to a poor prognosis in both hepatocellular carcinoma and colorectal cancer patients. [provided by RefSeq, Nov 2015]

IL36A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07809073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL36A	NM_014440.3 link	c.193C>A	p.Leu65Met	missense_variant	Exon 3 of 4	ENST00000259211.7	NP_055255.1	Q9UHA7
IL36A	XM_005263639.3 link	c.193C>A	p.Leu65Met	missense_variant	Exon 3 of 5		XP_005263696.1	Q9UHA7
IL36A	XM_011510965.2 link	c.193C>A	p.Leu65Met	missense_variant	Exon 3 of 5		XP_011509267.1	Q9UHA7
IL36A	XM_017003806.2 link	c.193C>A	p.Leu65Met	missense_variant	Exon 3 of 5		XP_016859295.1	Q9UHA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL36A	ENST00000259211.7 link	c.193C>A	p.Leu65Met	missense_variant	Exon 3 of 4	1	NM_014440.3	ENSP00000259211.6		Q9UHA7

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000441

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000236

AC:

AN:

249584

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.000637

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:

0.0000971

Gnomad OTH exome

AF:

0.000660

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.000648

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:

0.0000576

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000499

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000518

ESP6500AA

AF:

0.00152

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000174

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.193C>A (p.L65M) alteration is located in exon 3 (coding exon 3) of the IL36A gene. This alteration results from a C to A substitution at nucleotide position 193, causing the leucine (L) at amino acid position 65 to be replaced by a methionine (M). 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

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.2

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Benign

0.020

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.35

M_CAP

Benign

0.0057

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

REVEL

Benign

0.25

Sift

Benign

0.090

Sift4G

Benign

0.063

Polyphen

1.0

Vest4

0.36

MVP

0.16

MPC

0.33

ClinPred

0.039

GERP RS

0.085

Varity_R

0.10

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over