rs1131668

Positions:

• chr21-33262573-G-A
• chr21-33262573-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000874.5(IFNAR2):​c.853G>A​(p.Ala285Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 718,052 control chromosomes in the GnomAD database, including 48,370 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9532 hom., cov: 30)
  • Exomes 𝑓: 0.36 (38838 hom.)
• Consequence: IFNAR2 NM_000874.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.773

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-IL10RB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.6544243E-5).
• BP6: Variant 21-33262573-G-A is Benign according to our data. Variant chr21-33262573-G-A is described in ClinVar as [Benign]. Clinvar id is 402970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNAR2	NM_001289125.3	c.841-220G>A		intron_variant		ENST00000342136.9	NP_001276054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNAR2	ENST00000342136.9	c.841-220G>A		intron_variant		1	NM_001289125.3	ENSP00000343957.5
IFNAR2-IL10RB	ENST00000433395.7	c.710-5821G>A		intron_variant		5		ENSP00000388223.3

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53109 AN: 151582 Hom.: 9511 Cov.: 30

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.339

GnomAD3 exomes AF: 0.387 AC: 54809 AN: 141474 Hom.: 11368 AF XY: 0.388 AC XY: 30036 AN XY: 77316

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.592

Gnomad SAS exome AF: 0.471

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.360 AC: 203625 AN: 566350 Hom.: 38838 Cov.: 5 AF XY: 0.364 AC XY: 111628 AN XY: 306336

Gnomad4 AFR exome AF: 0.338

Gnomad4 AMR exome AF: 0.441

Gnomad4 ASJ exome AF: 0.317

Gnomad4 EAS exome AF: 0.566

Gnomad4 SAS exome AF: 0.464

Gnomad4 FIN exome AF: 0.353

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.356

GnomAD4 genome AF: 0.351 AC: 53174 AN: 151702 Hom.: 9532 Cov.: 30 AF XY: 0.359 AC XY: 26619 AN XY: 74068

Gnomad4 AFR AF: 0.335

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.342

Alfa AF: 0.248 Hom.: 897

Bravo AF: 0.351

TwinsUK AF: 0.310 AC: 1149

ALSPAC AF: 0.293 AC: 1129

ExAC AF: 0.243 AC: 22349

Asia WGS AF: 0.532 AC: 1845 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.5
DANN	Benign	0.82
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.36	.;T
MetaRNN	Benign	0.000047	T;T
MetaSVM	Benign	-0.95	T
PROVEAN	Benign	0.45	N;N
REVEL	Benign	0.025
Sift	Benign	0.71	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.60	P;P
Vest4		0.098
ClinPred		0.0023	T
GERP RS		0.56

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

Other links and lift over

dbSNP: rs1131668; hg19: chr21-34634878; COSMIC: COSV51613872; COSMIC: COSV51613872;