19-39248147-C-T

Variant names:

• chr19-39248147-C-T
• rs12979860
• ENST00000634967.1:c.152-152G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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
• Publications: 1602 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• 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 rank	MANE	Protein	UniProt
IFNL4	NR_074079.1	n.429-152G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNL4	ENST00000634967.1	c.152-152G>A		intron_variant	Intron 1 of 3	1		ENSP00000489559.1
IFNL4	ENST00000606380.2	c.152-152G>A		intron_variant	Intron 1 of 4	1		ENSP00000476098.2
IFNL4	ENST00000634680.1	c.151+282G>A		intron_variant	Intron 1 of 2	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

African (AFR) AF: 0.603 AC: 4365 AN: 7238

American (AMR) AF: 0.381 AC: 189 AN: 496

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 901 AN: 2460

East Asian (EAS) AF: 0.0542 AC: 98 AN: 1808

South Asian (SAS) AF: 0.206 AC: 1687 AN: 8172

European-Finnish (FIN) AF: 0.210 AC: 26 AN: 124

Middle Eastern (MID) AF: 0.281 AC: 220 AN: 784

European-Non Finnish (NFE) AF: 0.278 AC: 103171 AN: 370912

Other (OTH) AF: 0.272 AC: 3601 AN: 13226

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

African (AFR) AF: 0.603 AC: 25033 AN: 41510

American (AMR) AF: 0.374 AC: 5725 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1369 AN: 3472

East Asian (EAS) AF: 0.0713 AC: 369 AN: 5176

South Asian (SAS) AF: 0.227 AC: 1094 AN: 4828

European-Finnish (FIN) AF: 0.241 AC: 2553 AN: 10600

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21409 AN: 67956

Other (OTH) AF: 0.363 AC: 767 AN: 2114

Alfa AF: 0.348 Hom.: 14888

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

Mar 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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
PhyloP100		-2.8

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

Other links and lift over

dbSNP: rs12979860; hg19: chr19-39738787;