rs4803221

Variant names:

• chr19-39248489-C-G
• rs4803221
• ENST00000634967.1:c.91G>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 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 (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 rank	MANE	Protein	UniProt
IFNL4	NR_074079.1	n.368G>C		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.91G>C	p.Ala31Pro	missense_variant	Exon 1 of 4	1		ENSP00000489559.1
IFNL4	ENST00000606380.2	c.91G>C	p.Ala31Pro	missense_variant	Exon 1 of 5	1		ENSP00000476098.2
IFNL4	ENST00000634680.1	c.91G>C	p.Ala31Pro	missense_variant	Exon 1 of 3	1		ENSP00000489240.1

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

GnomAD2 exomes AF: 0.167 AC: 3 AN: 18 AF XY: 0.00

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

African (AFR) AF: 0.208 AC: 4773 AN: 22950

American (AMR) AF: 0.309 AC: 2601 AN: 8414

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 3075 AN: 14374

East Asian (EAS) AF: 0.0822 AC: 2179 AN: 26514

South Asian (SAS) AF: 0.161 AC: 3136 AN: 19494

European-Finnish (FIN) AF: 0.148 AC: 3120 AN: 21106

Middle Eastern (MID) AF: 0.183 AC: 532 AN: 2914

European-Non Finnish (NFE) AF: 0.201 AC: 184630 AN: 919830

Other (OTH) AF: 0.187 AC: 8181 AN: 43652

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

African (AFR) AF: 0.226 AC: 8767 AN: 38732

American (AMR) AF: 0.279 AC: 4246 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 743 AN: 3450

East Asian (EAS) AF: 0.0643 AC: 332 AN: 5166

South Asian (SAS) AF: 0.155 AC: 745 AN: 4800

European-Finnish (FIN) AF: 0.140 AC: 1477 AN: 10566

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13716 AN: 67738

Other (OTH) AF: 0.215 AC: 451 AN: 2102

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
PhyloP100		-5.4
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

Other links and lift over

dbSNP: rs4803221; hg19: chr19-39739129;