rs755873190

Variant names:

• chr21-33241966-T-G
• rs755873190
• NM_001289125.3:c.44T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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. 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.565
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

IFNAR2-IL10RB (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNAR2	NM_001289125.3	MANE Select	c.44T>G	p.Leu15Trp	missense	Exon 2 of 9	NP_001276054.1	P48551-1
	IFNAR2-IL10RB	NM_001414505.1		c.44T>G	p.Leu15Trp	missense	Exon 2 of 13	NP_001401434.1	H0Y3Z8
	IFNAR2	NM_207585.3		c.44T>G	p.Leu15Trp	missense	Exon 2 of 9	NP_997468.1	P48551-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNAR2	ENST00000342136.9	TSL:1 MANE Select	c.44T>G	p.Leu15Trp	missense	Exon 2 of 9	ENSP00000343957.5	P48551-1
	IFNAR2-IL10RB	ENST00000433395.7	TSL:5	c.44T>G	p.Leu15Trp	missense	Exon 2 of 13	ENSP00000388223.3	H0Y3Z8
	IFNAR2	ENST00000382264.7	TSL:1	c.44T>G	p.Leu15Trp	missense	Exon 2 of 9	ENSP00000371699.3	P48551-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 250076 AF XY: 0.0000148

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460544 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726602

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.000135 AC: 6 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111486

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.56
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.77		Loss of sheet (P = 0.0025)
MVP		0.80
MPC		0.34
ClinPred		0.77	D
GERP RS		3.1
Varity_R		0.30
gMVP		0.66
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs755873190; hg19: chr21-34614271;