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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000634967.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNL4	NR_074079.1		n.429-152G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNL4	ENST00000634967.1	TSL:1	c.152-152G>A		intron	N/A	ENSP00000489559.1
	IFNL4	ENST00000606380.2	TSL:1	c.152-152G>A		intron	N/A	ENSP00000476098.2
	IFNL4	ENST00000634680.1	TSL:1	c.151+282G>A		intron	N/A	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

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	-	boceprevir, peginterferon alfa-2a, peginterferon alfa-2b and ribavirin response - Efficacy (1)
-	-	-	peginterferon alfa-2a, peginterferon alfa-2b, and ribavirin response - Efficacy (1)
-	-	-	peginterferon alfa-2a, peginterferon alfa-2b, ribavirin, and telaprevir response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

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;