rs4803222

Variant names:

• chr19-39248713-G-C
• rs4803222
• ENST00000634967.1:c.-134C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 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=-0.88).
• 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 rank	MANE	Protein	UniProt
IFNL4	NR_074079.1	n.144C>G		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNL4	ENST00000634967.1	c.-134C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	1		ENSP00000489559.1
IFNL4	ENST00000634967.1	c.-134C>G		5_prime_UTR_variant	Exon 1 of 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

African (AFR) AF: 0.282 AC: 4185 AN: 14840

American (AMR) AF: 0.366 AC: 2886 AN: 7894

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 4422 AN: 11748

East Asian (EAS) AF: 0.0874 AC: 2160 AN: 24726

South Asian (SAS) AF: 0.202 AC: 2209 AN: 10950

European-Finnish (FIN) AF: 0.243 AC: 5088 AN: 20938

Middle Eastern (MID) AF: 0.298 AC: 641 AN: 2154

European-Non Finnish (NFE) AF: 0.273 AC: 151667 AN: 555608

Other (OTH) AF: 0.263 AC: 8044 AN: 30534

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

African (AFR) AF: 0.292 AC: 12132 AN: 41528

American (AMR) AF: 0.342 AC: 5225 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1351 AN: 3472

East Asian (EAS) AF: 0.0709 AC: 367 AN: 5176

South Asian (SAS) AF: 0.211 AC: 1021 AN: 4828

European-Finnish (FIN) AF: 0.221 AC: 2337 AN: 10598

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

European-Non Finnish (NFE) AF: 0.297 AC: 20221 AN: 67974

Other (OTH) AF: 0.296 AC: 626 AN: 2112

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
PhyloP100		-0.28

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

Other links and lift over

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