21-33341445-A-T

Variant names:

• chr21-33341445-A-T
• rs1012334
• NM_000629.3:c.376+271A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000629.3(IFNAR1):​c.376+271A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 152,034 control chromosomes in the GnomAD database, including 25,006 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25006 hom., cov: 32)
• Consequence: IFNAR1 NM_000629.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 10 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000629.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNAR1	NM_000629.3	MANE Select	c.376+271A>T		intron	N/A	NP_000620.2
	IFNAR1	NM_001384498.1		c.376+271A>T		intron	N/A	NP_001371427.1
	IFNAR1	NM_001384503.1		c.376+271A>T		intron	N/A	NP_001371432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNAR1	ENST00000270139.8	TSL:1 MANE Select	c.376+271A>T		intron	N/A	ENSP00000270139.3
	IFNAR1	ENST00000700099.1		n.728A>T		non_coding_transcript_exon	Exon 3 of 3
	IFNAR1	ENST00000703557.1		c.376+271A>T		intron	N/A	ENSP00000515373.1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84449 AN: 151916 Hom.: 24951 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.547

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.556 AC: 84566 AN: 152034 Hom.: 25006 Cov.: 32 AF XY: 0.550 AC XY: 40860 AN XY: 74316

African (AFR) AF: 0.778 AC: 32266 AN: 41496

American (AMR) AF: 0.499 AC: 7637 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1638 AN: 3472

East Asian (EAS) AF: 0.412 AC: 2122 AN: 5154

South Asian (SAS) AF: 0.435 AC: 2100 AN: 4828

European-Finnish (FIN) AF: 0.455 AC: 4799 AN: 10540

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.474 AC: 32204 AN: 67938

Other (OTH) AF: 0.553 AC: 1165 AN: 2108

Alfa AF: 0.505 Hom.: 2705

Bravo AF: 0.569

Asia WGS AF: 0.449 AC: 1564 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.75
DANN	Benign	0.49
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs1012334; hg19: chr21-34713751;