19-39244283-A-G

Position:

• chr19-39244283-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172139.4(IFNL3):​c.259-126T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,480,780 control chromosomes in the GnomAD database, including 59,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6936 hom., cov: 29)
  • Exomes 𝑓: 0.28 (52993 hom.)
• Consequence: IFNL3 NM_172139.4 intron
• Clinical Significance: drug response reviewed by expert panel O:3
• Conservation: PhyloP100: -0.860

Genes affected

IFNL3 (HGNC:18365): (interferon lambda 3) This gene encodes a cytokine distantly related to type I interferons and the IL-10 family. This gene, interleukin 28A (IL28A), and interleukin 29 (IL29) are three closely related cytokine genes that form a cytokine gene cluster on a chromosomal region mapped to 19q13. Expression of the cytokines encoded by the three genes can be induced by viral infection. All three cytokines have been shown to interact with a heterodimeric class II cytokine receptor that consists of interleukin 10 receptor, beta (IL10RB) and interleukin 28 receptor, alpha (IL28RA). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNL3	NM_172139.4	c.259-126T>C		intron_variant		ENST00000413851.3	NP_742151.2
IFNL3	NM_001346937.2	c.271-126T>C		intron_variant			NP_001333866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL3	ENST00000413851.3	c.259-126T>C		intron_variant		1	NM_172139.4	ENSP00000409000	A2
IFNL3	ENST00000613087.5	c.271-126T>C		intron_variant		1		ENSP00000481633	P4

Frequencies

GnomAD3 genomes AF: 0.297 AC: 44904 AN: 151146 Hom.: 6925 Cov.: 29

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.0710

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.301

GnomAD4 exome AF: 0.279 AC: 370626 AN: 1329516 Hom.: 52993 Cov.: 23 AF XY: 0.277 AC XY: 181980 AN XY: 656916

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.0797

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.297 AC: 44959 AN: 151264 Hom.: 6936 Cov.: 29 AF XY: 0.291 AC XY: 21496 AN XY: 73894

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.0713

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.298

Alfa AF: 0.301 Hom.: 4427

Bravo AF: 0.310

Asia WGS AF: 0.157 AC: 549 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:3

Revision: reviewed by expert panel

Submissions by phenotype

peginterferon alfa-2a response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

ribavirin response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

peginterferon alfa-2b response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.8
DANN	Benign	0.68

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: rs11881222; hg19: chr19-39734923; COSMIC: COSV69829920; COSMIC: COSV69829920;