NM_000629.3:c.76+545A>G

Variant names:

• chr21-33325676-A-G
• rs2856968
• NM_000629.3:c.76+545A>G

Variant summary

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

The NM_000629.3(IFNAR1):​c.76+545A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,050 control chromosomes in the GnomAD database, including 11,204 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 0.38 (11204 hom., cov: 32)
• Consequence: IFNAR1 NM_000629.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.502
• 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.403 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.76+545A>G		intron	N/A	NP_000620.2
	IFNAR1	NM_001384498.1		c.76+545A>G		intron	N/A	NP_001371427.1
	IFNAR1	NM_001384503.1		c.76+545A>G		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.76+545A>G		intron	N/A	ENSP00000270139.3
	IFNAR1	ENST00000873010.1		c.76+545A>G		intron	N/A	ENSP00000543069.1
	IFNAR1	ENST00000703557.1		c.76+545A>G		intron	N/A	ENSP00000515373.1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57882 AN: 151932 Hom.: 11200 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.399

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

GnomAD4 genome AF: 0.381 AC: 57901 AN: 152050 Hom.: 11204 Cov.: 32 AF XY: 0.380 AC XY: 28242 AN XY: 74312

African (AFR) AF: 0.320 AC: 13276 AN: 41464

American (AMR) AF: 0.412 AC: 6287 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1229 AN: 3464

East Asian (EAS) AF: 0.369 AC: 1913 AN: 5178

South Asian (SAS) AF: 0.405 AC: 1955 AN: 4822

European-Finnish (FIN) AF: 0.402 AC: 4247 AN: 10574

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27626 AN: 67958

Other (OTH) AF: 0.402 AC: 847 AN: 2108

Alfa AF: 0.250 Hom.: 613

Bravo AF: 0.378

Asia WGS AF: 0.365 AC: 1269 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.2
DANN	Benign	0.81
PhyloP100		-0.50
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: rs2856968; hg19: chr21-34697981;