Genetic Variant IFNAR1:p.Gln34His (chr21-33335549-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000629.3(IFNAR1):c.102A>C(p.Gln34His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q34Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IFNAR1
NM_000629.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.482

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: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

IFNAR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29531795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNAR1	NM_000629.3 link	c.102A>C	p.Gln34His	missense_variant	Exon 2 of 11	ENST00000270139.8	NP_000620.2	P17181-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNAR1	ENST00000270139.8 link	c.102A>C	p.Gln34His	missense_variant	Exon 2 of 11	1	NM_000629.3	ENSP00000270139.3		P17181-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449906

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721512

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33122

American (AMR)

AF:

0.00

AC:

AN:

43616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25974

East Asian (EAS)

AF:

0.00

AC:

AN:

39426

South Asian (SAS)

AF:

0.00

AC:

AN:

84524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1104262

Other (OTH)

AF:

0.00

AC:

AN:

59918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.060

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.60

T;.

M_CAP

Benign

0.053

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

0.48

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.4

N;D

REVEL

Benign

0.24

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.26

MutPred

0.49

Loss of ubiquitination at K31 (P = 0.0997);Loss of ubiquitination at K31 (P = 0.0997);

MVP

0.84

MPC

0.086

ClinPred

0.40

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.42

Mutation Taster

=81/19

polymorphism

(source)

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

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21-33335549-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over