rs2257167

chr21-33343393-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000629.3(IFNAR1):c.502G>C(p.Val168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,610,902 control chromosomes in the GnomAD database, including 21,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. V168V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2330 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18918 hom.)
• Consequence: IFNAR1 NM_000629.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.195

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042078197).
• BP6: Variant 21-33343393-G-C is Benign according to our data. Variant chr21-33343393-G-C is described in ClinVar as [Benign]. Clinvar id is 1170802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNAR1	NM_000629.3	c.502G>C	p.Val168Leu	missense_variant	4/11	ENST00000270139.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNAR1	ENST00000270139.8	c.502G>C	p.Val168Leu	missense_variant	4/11	1	NM_000629.3	P4

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24799 AN: 152018 Hom.: 2322 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.0887

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.180

GnomAD3 exomes AF: 0.185 AC: 46302 AN: 250954 Hom.: 5194 AF XY: 0.186 AC XY: 25166 AN XY: 135658

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.368

Gnomad SAS exome AF: 0.261

Gnomad FIN exome AF: 0.0919

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.150 AC: 218622 AN: 1458768 Hom.: 18918 Cov.: 30 AF XY: 0.153 AC XY: 111246 AN XY: 725878

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.328

Gnomad4 SAS exome AF: 0.260

Gnomad4 FIN exome AF: 0.0952

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.163 AC: 24812 AN: 152134 Hom.: 2330 Cov.: 33 AF XY: 0.165 AC XY: 12282 AN XY: 74386

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.375

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.0887

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.186

Alfa AF: 0.146 Hom.: 587

Bravo AF: 0.175

TwinsUK AF: 0.132 AC: 488

ALSPAC AF: 0.131 AC: 506

ESP6500AA AF: 0.159 AC: 701

ESP6500EA AF: 0.135 AC: 1159

ExAC AF: 0.182 AC: 22091

Asia WGS AF: 0.313 AC: 1087 AN: 3472

EpiCase AF: 0.147

EpiControl AF: 0.144

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied by a panel of primary immunodeficiencies. Number of patients: 38. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.092
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Polyphen		0.76	P
Vest4		0.037
MPC		0.14
ClinPred		0.0037	T
GERP RS		0.84
Varity_R		0.36
gMVP		0.33

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: rs2257167; hg19: chr21-34715699; COSMIC: COSV54251383;