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

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

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNAR1	NM_000629.3	c.77-22T>G		intron_variant	Intron 1 of 10	ENST00000270139.8	NP_000620.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNAR1	ENST00000270139.8	c.77-22T>G		intron_variant	Intron 1 of 10	1	NM_000629.3	ENSP00000270139.3

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

Gnomad4 AFR exome AF: 0.314 AC: 9324 AN: 29682

Gnomad4 AMR exome AF: 0.401 AC: 15917 AN: 39710

Gnomad4 ASJ exome AF: 0.345 AC: 8448 AN: 24510

Gnomad4 EAS exome AF: 0.328 AC: 12542 AN: 38250

Gnomad4 SAS exome AF: 0.408 AC: 31905 AN: 78268

Gnomad4 FIN exome AF: 0.403 AC: 21212 AN: 52632

Gnomad4 NFE exome AF: 0.391 AC: 379128 AN: 969558

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.320 AC: 0.31992 AN: 0.31992

Gnomad4 AMR AF: 0.411 AC: 0.411152 AN: 0.411152

Gnomad4 ASJ AF: 0.355 AC: 0.355415 AN: 0.355415

Gnomad4 EAS AF: 0.370 AC: 0.369599 AN: 0.369599

Gnomad4 SAS AF: 0.407 AC: 0.407446 AN: 0.407446

Gnomad4 FIN AF: 0.403 AC: 0.402804 AN: 0.402804

Gnomad4 NFE AF: 0.406 AC: 0.40586 AN: 0.40586

Gnomad4 OTH AF: 0.402 AC: 0.401709 AN: 0.401709

Alfa AF: 0.389 Hom.: 2209

Bravo AF: 0.378

Asia WGS AF: 0.365 AC: 1271 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 60% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.77
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

Publications

LitVar

Other links and lift over

dbSNP: rs2243592; hg19: chr21-34707808;