21-33262573-G-T

Variant names:

• chr21-33262573-G-T
• rs1131668
• ENST00000382264.7:c.853G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000874.5(IFNAR2):​c.853G>T​(p.Ala285Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000882 in 566,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A285T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: IFNAR2 NM_000874.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.773
• Publications: 31 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054858863).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000874.5. 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.841-220G>T		intron	N/A	NP_001276054.1	P48551-1
	IFNAR2	NM_000874.5		c.853G>T	p.Ala285Ser	missense	Exon 9 of 9	NP_000865.2
	IFNAR2	NM_207584.3		c.853G>T	p.Ala285Ser	missense	Exon 9 of 9	NP_997467.1	P48551-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNAR2	ENST00000382264.7	TSL:1	c.853G>T	p.Ala285Ser	missense	Exon 9 of 9	ENSP00000371699.3	P48551-2
	IFNAR2	ENST00000404220.7	TSL:1	c.853G>T	p.Ala285Ser	missense	Exon 9 of 9	ENSP00000384309.2	P48551-2
	IFNAR2	ENST00000342136.9	TSL:1 MANE Select	c.841-220G>T		intron	N/A	ENSP00000343957.5	P48551-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000141 AC: 2 AN: 141474 AF XY: 0.0000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000149

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000882 AC: 5 AN: 566620 Hom.: 0 Cov.: 5 AF XY: 0.00000979 AC XY: 3 AN XY: 306476

African (AFR) AF: 0.00 AC: 0 AN: 15992

American (AMR) AF: 0.00 AC: 0 AN: 34562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20166

East Asian (EAS) AF: 0.00 AC: 0 AN: 32162

South Asian (SAS) AF: 0.00 AC: 0 AN: 63576

European-Finnish (FIN) AF: 0.0000281 AC: 1 AN: 35596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2908

European-Non Finnish (NFE) AF: 0.0000121 AC: 4 AN: 330738

Other (OTH) AF: 0.00 AC: 0 AN: 30920

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000470 Hom.: 897

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.5
DANN	Benign	0.80
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.77
PROVEAN	Benign	0.43	N
REVEL	Benign	0.026
Sift	Benign	0.73	T
Sift4G	Benign	0.54	T
Polyphen		0.25	B
Vest4		0.13
MutPred		0.49		Gain of sheet (P = 0.0125)
MVP		0.16
ClinPred		0.041	T
GERP RS		0.56
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1131668; hg19: chr21-34634878;