21-33325069-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000629.3(IFNAR1):c.14T>G(p.Leu5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L5L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFNAR1 NM_000629.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38450247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNAR1	NM_000629.3	c.14T>G	p.Leu5Arg	missense_variant	1/11	ENST00000270139.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNAR1	ENST00000270139.8	c.14T>G	p.Leu5Arg	missense_variant	1/11	1	NM_000629.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Sep 08, 2023

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 5 of the IFNAR1 protein (p.Leu5Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IFNAR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1917845). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	0.21
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.61	T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.98	D;.
Vest4		0.70
MutPred		0.67		Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);
MVP		0.69
MPC		0.081
ClinPred		0.60	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.42
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-34697374;