21-33325086-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000629.3(IFNAR1):c.31C>G(p.Leu11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,458,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: IFNAR1 NM_000629.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.215

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08614287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNAR1	NM_000629.3	c.31C>G	p.Leu11Val	missense_variant	1/11	ENST00000270139.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNAR1	ENST00000270139.8	c.31C>G	p.Leu11Val	missense_variant	1/11	1	NM_000629.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000661 AC: 16 AN: 242034 Hom.: 0 AF XY: 0.0000303 AC XY: 4 AN XY: 131956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000471

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000130 AC: 19 AN: 1458530 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 6 AN XY: 725432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000428

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

This sequence change replaces leucine with valine at codon 11 of the IFNAR1 protein (p.Leu11Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs759467737, ExAC 0.06%). This variant has not been reported in the literature in individuals affected with IFNAR1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.092	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.63	T;.
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.91	D;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.062
Sift	Benign	0.062	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.72	P;.
Vest4		0.27
MutPred		0.42		Gain of catalytic residue at L11 (P = 0.0021);Gain of catalytic residue at L11 (P = 0.0021);
MVP		0.64
MPC		0.25
ClinPred		0.098	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.081
gMVP		0.24

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: rs759467737; hg19: chr21-34697391;