21-33335502-T-G

Variant names:

• chr21-33335502-T-G
• rs2243592
• NM_000629.3:c.77-22T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000629.3(IFNAR1):​c.77-22T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,444,442 control chromosomes in the GnomAD database, including 109,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.38 (11183 hom., cov: 31)
  • Exomes 𝑓: 0.39 (98791 hom.)
• Consequence: IFNAR1 NM_000629.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.54
• Publications: 11 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 -14 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 21-33335502-T-G is Benign according to our data. Variant chr21-33335502-T-G is described in ClinVar as Benign. ClinVar VariationId is 2688073.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.77-22T>G		intron	N/A	NP_000620.2
	IFNAR1	NM_001384498.1		c.77-22T>G		intron	N/A	NP_001371427.1
	IFNAR1	NM_001384503.1		c.77-22T>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.77-22T>G		intron	N/A	ENSP00000270139.3
	IFNAR1	ENST00000703557.1		c.77-22T>G		intron	N/A	ENSP00000515373.1
	IFNAR1	ENST00000652450.2		c.-131-22T>G		intron	N/A	ENSP00000498654.1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57830 AN: 151900 Hom.: 11179 Cov.: 31

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.399

GnomAD2 exomes AF: 0.394 AC: 90086 AN: 228704 AF XY: 0.396

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.360

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.389 AC: 502273 AN: 1292424 Hom.: 98791 Cov.: 18 AF XY: 0.390 AC XY: 253276 AN XY: 649228

African (AFR) AF: 0.314 AC: 9324 AN: 29682

American (AMR) AF: 0.401 AC: 15917 AN: 39710

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 8448 AN: 24510

East Asian (EAS) AF: 0.328 AC: 12542 AN: 38250

South Asian (SAS) AF: 0.408 AC: 31905 AN: 78268

European-Finnish (FIN) AF: 0.403 AC: 21212 AN: 52632

Middle Eastern (MID) AF: 0.437 AC: 2374 AN: 5432

European-Non Finnish (NFE) AF: 0.391 AC: 379128 AN: 969558

Other (OTH) AF: 0.394 AC: 21423 AN: 54382

GnomAD4 genome AF: 0.381 AC: 57849 AN: 152018 Hom.: 11183 Cov.: 31 AF XY: 0.380 AC XY: 28231 AN XY: 74292

African (AFR) AF: 0.320 AC: 13269 AN: 41476

American (AMR) AF: 0.411 AC: 6275 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1234 AN: 3472

East Asian (EAS) AF: 0.370 AC: 1916 AN: 5184

South Asian (SAS) AF: 0.407 AC: 1959 AN: 4808

European-Finnish (FIN) AF: 0.403 AC: 4252 AN: 10556

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

European-Non Finnish (NFE) AF: 0.406 AC: 27579 AN: 67952

Other (OTH) AF: 0.402 AC: 846 AN: 2106

Alfa AF: 0.389 Hom.: 2209

Bravo AF: 0.378

Asia WGS AF: 0.365 AC: 1271 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		1.5
BranchPoint Hunter		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2243592; hg19: chr21-34707808;