Genetic Variant IFNAR1:p.Pro18_Trp19del (chr21-33325119-TCCGCAG-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The ENST00000270139.8(IFNAR1):c.52_57delCCGCAG(p.Pro18_Trp19del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000856 in 1,611,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

IFNAR1
ENST00000270139.8 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.72

Publications

0 publications found

Variant links:

Genes affected

IFNAR1 (HGNC:5432): (interferon alpha and beta receptor subunit 1) 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 and functions as an antiviral factor. [provided by RefSeq, Jul 2020]

IFNAR1 Gene-Disease associations (from GenCC):

immunodeficiency 106, susceptibility to viral infections
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

IFNAR1 links:

ENSG00000289238 (HGNC:):

ENSG00000289238 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in ENST00000270139.8.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000270139.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFNAR1	NM_000629.3	MANE Select	c.71_76delCCGCAG	p.Ala24_Ala25del	disruptive_inframe_deletion splice_region	Exon 1 of 11	NP_000620.2
IFNAR1	NM_001384498.1		c.71_76delCCGCAG	p.Ala24_Ala25del	disruptive_inframe_deletion splice_region	Exon 1 of 12	NP_001371427.1
IFNAR1	NM_001384503.1		c.71_76delCCGCAG	p.Ala24_Ala25del	disruptive_inframe_deletion splice_region	Exon 1 of 11	NP_001371432.1	A0A994J6F6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFNAR1	ENST00000270139.8	TSL:1 MANE Select	c.52_57delCCGCAG	p.Pro18_Trp19del	conservative_inframe_deletion	Exon 1 of 11	ENSP00000270139.3	P17181-1
IFNAR1	ENST00000873010.1		c.52_57delCCGCAG	p.Pro18_Trp19del	conservative_inframe_deletion	Exon 1 of 12	ENSP00000543069.1
IFNAR1	ENST00000703557.1		c.52_57delCCGCAG	p.Pro18_Trp19del	conservative_inframe_deletion	Exon 1 of 11	ENSP00000515373.1	A0A994J6F6

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000534

AC:

AN:

243414

AF XY:

0.0000226

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000101

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000870

AC:

127

AN:

1459228

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

725900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.0000224

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85992

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52684

Middle Eastern (MID)

AF:

0.000198

AC:

AN:

5062

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1111542

Other (OTH)

AF:

0.0000664

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000756

EpiCase

AF:

0.000164

EpiControl

AF:

0.000179

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=127/73

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over