19-39248147-C-T

Position:

• chr19-39248147-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

The ENST00000634967.1(IFNL4):​c.152-152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 557,362 control chromosomes in the GnomAD database, including 30,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13046 hom., cov: 33)
  • Exomes 𝑓: 0.28 (17227 hom.)
• Consequence: IFNL4 ENST00000634967.1 intron
• Clinical Significance: drug response reviewed by expert panel B:1 O:3
• Conservation: PhyloP100: -2.79

Genes affected

IFNL4 (HGNC:44480): (interferon lambda 4 (gene/pseudogene)) This gene is a polymorphic pseudogene which, in some humans, encodes the interferon (IFN) lambda 4 protein. Humans are polymorphic for the dinucleotide TT/deltaG allele. Compared to the ancestral state in non-human primates, the TT allele produces a frameshift in the coding region of this gene which is predicted to induce nonsense-mediated mRNA decay. This allele, and an allele in the first intron of this gene, have experienced a rapid increase in frequency and show indications of positive selection. The ancestral states of these alleles are associated with an impaired ability to clear hepatitis C virus. This gene, like other type III interferons (IFNs), interacts with the IFN lambda receptor complex (IFNLR) whose signaling is generally restricted to epithelial cells. This gene resides in a cluster of four type III IFN genes and at least two pseudogenes on chromosome 19q13.2. In general, interferons are produced in response to viral infection and block viral replication and propagation to uninfected cells by activating the JAK-STAT pathway and up-regulating antiviral genes. Multiple alternatively spliced transcripts have been described for this gene but their biological validity and protein coding status is still being ascertained. [provided by RefSeq, May 2017]

IFNL4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-39248147-C-T is Benign according to our data. Variant chr19-39248147-C-T is described in ClinVar as [drug_response]. Clinvar id is 225949.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, drug_response=3}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNL4	NR_074079.1	n.429-152G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL4	ENST00000634967.1	c.152-152G>A		intron_variant		1		ENSP00000489559.1
IFNL4	ENST00000606380.2	c.152-152G>A		intron_variant		1		ENSP00000476098.2
IFNL4	ENST00000634680.1	c.151+282G>A		intron_variant		1		ENSP00000489240.1

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58681 AN: 152024 Hom.: 13013 Cov.: 33

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.0709

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.367

GnomAD4 exome AF: 0.282 AC: 114258 AN: 405220 Hom.: 17227 AF XY: 0.283 AC XY: 53743 AN XY: 189990

Gnomad4 AFR exome AF: 0.603

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.0542

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.210

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.386 AC: 58763 AN: 152142 Hom.: 13046 Cov.: 33 AF XY: 0.377 AC XY: 28052 AN XY: 74398

Gnomad4 AFR AF: 0.603

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.0713

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.363

Alfa AF: 0.328 Hom.: 6674

Bravo AF: 0.407

Asia WGS AF: 0.191 AC: 669 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Benign:1 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

boceprevir, peginterferon alfa-2a, peginterferon alfa-2b and ribavirin response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

peginterferon alfa-2a, peginterferon alfa-2b, ribavirin, and telaprevir response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

peginterferon alfa-2a, peginterferon alfa-2b, and ribavirin response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.64
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12979860; hg19: chr19-39738787;