rs1051393

chr21-33241950-T-Gchr21-33241950-T-Achr21-33241950-T-C

Variant summary

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

The NM_001289125.3(IFNAR2):c.28T>G(p.Phe10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,606,830 control chromosomes in the GnomAD database, including 95,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F10I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8284 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86938 hom.)
• Consequence: IFNAR2 NM_001289125.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.92

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=3.302767E-5).
• BP6: Variant 21-33241950-T-G is Benign according to our data. Variant chr21-33241950-T-G is described in ClinVar as [Benign]. Clinvar id is 1170800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNAR2	NM_001289125.3	c.28T>G	p.Phe10Val	missense_variant	2/9	ENST00000342136.9
IFNAR2-IL10RB	NM_001414505.1	c.28T>G	p.Phe10Val	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNAR2	ENST00000342136.9	c.28T>G	p.Phe10Val	missense_variant	2/9	1	NM_001289125.3	P2

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48202 AN: 151950 Hom.: 8274 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.383 AC: 95264 AN: 248934 Hom.: 19832 AF XY: 0.386 AC XY: 51937 AN XY: 134618

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.582

Gnomad SAS exome AF: 0.475

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.337 AC: 490087 AN: 1454762 Hom.: 86938 Cov.: 31 AF XY: 0.341 AC XY: 247021 AN XY: 723956

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.467

Gnomad4 ASJ exome AF: 0.321

Gnomad4 EAS exome AF: 0.565

Gnomad4 SAS exome AF: 0.470

Gnomad4 FIN exome AF: 0.385

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.317 AC: 48244 AN: 152068 Hom.: 8284 Cov.: 32 AF XY: 0.329 AC XY: 24420 AN XY: 74322

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.326

Gnomad4 OTH AF: 0.315

Alfa AF: 0.322 Hom.: 12293

Bravo AF: 0.311

TwinsUK AF: 0.315 AC: 1168

ALSPAC AF: 0.299 AC: 1151

ESP6500AA AF: 0.188 AC: 828

ESP6500EA AF: 0.317 AC: 2726

ExAC AF: 0.378 AC: 45947

Asia WGS AF: 0.519 AC: 1801 AN: 3478

EpiCase AF: 0.333

EpiControl AF: 0.337

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 69% of patients studied by a panel of primary immunodeficiencies. Number of patients: 66. Only high quality variants are reported. -

Immunodeficiency 45 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Mortality risk in patients with severe coronavirus disease (COVID-19) Other:1

association, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.0080
Dann	Benign	0.56
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0024	N
MetaRNN	Benign	0.000033	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.3	N;N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N;N;N;N;N
REVEL	Benign	0.0050
Sift	Benign	0.77	T;T;T;T;T
Sift4G	Benign	0.62	T;T;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.046
MPC		0.046
ClinPred		0.0044	T
GERP RS		-7.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.35

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: rs1051393; hg19: chr21-34614255; COSMIC: COSV59747499; COSMIC: COSV59747499;