21-33241955-A-T

Variant names:

• chr21-33241955-A-T
• NM_001289125.3:c.33A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001289125.3(IFNAR2):​c.33A>T​(p.Arg11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R11T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFNAR2 NM_001289125.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.471
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 45

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

IFNAR2-IL10RB (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16128653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNAR2	NM_001289125.3	c.33A>T	p.Arg11Ser	missense_variant	Exon 2 of 9	ENST00000342136.9	NP_001276054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNAR2	ENST00000342136.9	c.33A>T	p.Arg11Ser	missense_variant	Exon 2 of 9	1	NM_001289125.3	ENSP00000343957.5
IFNAR2-IL10RB	ENST00000433395.7	c.33A>T	p.Arg11Ser	missense_variant	Exon 2 of 13	5		ENSP00000388223.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with IFNAR2-related conditions. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 11 of the IFNAR2 protein (p.Arg11Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.1
DANN	Benign	0.96
DEOGEN2	Benign	0.23	.;.;T;.;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.48	.;T;.;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;L;.
PhyloP100		0.47
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.40	B;B;B;B;.
Vest4		0.18
MutPred		0.52		Gain of disorder (P = 0.0966);Gain of disorder (P = 0.0966);Gain of disorder (P = 0.0966);Gain of disorder (P = 0.0966);.;
MVP		0.43
MPC		0.065
ClinPred		0.14	T
GERP RS		-0.16
Varity_R		0.18
gMVP		0.54
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

hg19: chr21-34614260;