rs4803222

Positions:

• chr19-39248713-G-C

Variant summary

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

The ENST00000634967.1(IFNL4):​c.-134C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 831,574 control chromosomes in the GnomAD database, including 31,726 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (6554 hom., cov: 32)
  • Exomes 𝑓: 0.27 (25172 hom.)
• Consequence: IFNL4 ENST00000634967.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.278

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNL4	NR_074079.1	n.144C>G		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL4	ENST00000634967.1	c.-134C>G		5_prime_UTR_premature_start_codon_gain_variant	1/4	1		ENSP00000489559.1
IFNL4	ENST00000634967.1	c.-134C>G		5_prime_UTR_variant	1/4	1		ENSP00000489559.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43651 AN: 152064 Hom.: 6549 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.0705

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.300

GnomAD4 exome AF: 0.267 AC: 181302 AN: 679392 Hom.: 25172 Cov.: 9 AF XY: 0.268 AC XY: 88024 AN XY: 328300

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.376

Gnomad4 EAS exome AF: 0.0874

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.273

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.287 AC: 43698 AN: 152182 Hom.: 6554 Cov.: 32 AF XY: 0.281 AC XY: 20916 AN XY: 74410

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.0709

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.296

Alfa AF: 0.302 Hom.: 867

Bravo AF: 0.299

Asia WGS AF: 0.149 AC: 522 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.39

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: rs4803222; hg19: chr19-39739353; COSMIC: COSV69830233; COSMIC: COSV69830233;