rs4803221

Positions:

• chr19-39248489-C-G
• chr19-39248489-C-T

Variant summary

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

The ENST00000634967.1(IFNL4):​c.91G>C​(p.Ala31Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,228,226 control chromosomes in the GnomAD database, including 24,468 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/8 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3243 hom., cov: 33)
  • Exomes 𝑓: 0.20 (21225 hom.)
• Consequence: IFNL4 ENST00000634967.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.35

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 (MetaRNN=0.0014515817).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNL4	NR_074079.1	n.368G>C		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL4	ENST00000634967.1	c.91G>C	p.Ala31Pro	missense_variant	1/4	1		ENSP00000489559	P5
IFNL4	ENST00000606380.2	c.91G>C	p.Ala31Pro	missense_variant	1/5	1		ENSP00000476098	A2
IFNL4	ENST00000634680.1	c.91G>C	p.Ala31Pro	missense_variant	1/3	1		ENSP00000489240	A2

Frequencies

GnomAD3 genomes AF: 0.206 AC: 30712 AN: 148866 Hom.: 3244 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.217

GnomAD3 exomes AF: 0.167 AC: 3 AN: 18 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8

Gnomad AFR exome AF: 0.250

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.197 AC: 212227 AN: 1079248 Hom.: 21225 Cov.: 32 AF XY: 0.197 AC XY: 100533 AN XY: 509520

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.309

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.0822

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.206 AC: 30738 AN: 148978 Hom.: 3243 Cov.: 33 AF XY: 0.201 AC XY: 14668 AN XY: 72800

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.279

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.0643

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.215

Alfa AF: 0.207 Hom.: 389

Bravo AF: 0.215

TwinsUK AF: 0.209 AC: 775

ALSPAC AF: 0.198 AC: 763

ExAC AF: 0.0539 AC: 304

Asia WGS AF: 0.110 AC: 386 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.011
DANN	Benign	0.90
DEOGEN2	Benign	0.0095	T
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0015	T
Vest4		0.11
GERP RS		-5.7

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: rs4803221; hg19: chr19-39739129;