Variant 21-33241966-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001289125.3(IFNAR2):c.44T>G(p.Leu15Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

IFNAR2
NM_001289125.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.565

Variant links:

Genes affected

IFNAR2 (HGNC:5433): (interferon alpha and beta receptor subunit 2) The protein encoded by this gene is a type I membrane protein that forms one of the two chains of a receptor for interferons alpha and beta. Binding and activation of the receptor stimulates Janus protein kinases, which in turn phosphorylate several proteins, including STAT1 and STAT2. The protein belongs to the type II cytokine receptor family. Mutations in this gene are associated with Immunodeficiency 45. [provided by RefSeq, Jul 2020]

IFNAR2 links:

IFNAR2-IL10RB (HGNC:):

IFNAR2-IL10RB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNAR2	NM_001289125.3 linkuse as main transcript	c.44T>G	p.Leu15Trp	missense_variant	2/9	ENST00000342136.9	NP_001276054.1
IFNAR2-IL10RB	NM_001414505.1 linkuse as main transcript	c.44T>G	p.Leu15Trp	missense_variant	2/13		NP_001401434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNAR2	ENST00000342136.9 linkuse as main transcript	c.44T>G	p.Leu15Trp	missense_variant	2/9	1	NM_001289125.3	ENSP00000343957	P2	P48551-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250076

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460544

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726602

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000135

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 17, 2022

This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 15 of the IFNAR2 protein (p.Leu15Trp). This variant is present in population databases (rs755873190, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with IFNAR2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.69

.;.;D;.;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.45

.;T;.;T;T

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.2

M;M;M;M;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.5

D;D;D;D;D

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;P;P;.

Vest4

0.37

MutPred

0.77

Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);.;

MVP

0.80

MPC

0.34

ClinPred

0.77

GERP RS

3.1

Varity_R

0.30

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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