19-39247226-C-G

Variant names:

• chr19-39247226-C-G
• rs12971396
• ENST00000634967.1:c.304G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000634967.1(IFNL4):​c.304G>C​(p.Ala102Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,230,816 control chromosomes in the GnomAD database, including 24,612 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 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 0.20 (3368 hom., cov: 32)
  • Exomes 𝑓: 0.20 (21244 hom.)
• Consequence: IFNL4 ENST00000634967.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 15 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.271 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.725G>C		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNL4	ENST00000634967.1	TSL:1	c.304G>C	p.Ala102Pro	missense	Exon 4 of 4	ENSP00000489559.1
	IFNL4	ENST00000634680.1	TSL:1	c.232G>C	p.Ala78Pro	missense	Exon 3 of 3	ENSP00000489240.1
	IFNL4	ENST00000606380.2	TSL:1	c.*76G>C		3_prime_UTR	Exon 5 of 5	ENSP00000476098.2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31148 AN: 152032 Hom.: 3365 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.0636

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.250 AC: 9 AN: 36 AF XY: 0.250

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.196 AC: 211639 AN: 1078666 Hom.: 21244 Cov.: 31 AF XY: 0.197 AC XY: 100310 AN XY: 509256

African (AFR) AF: 0.215 AC: 4901 AN: 22840

American (AMR) AF: 0.310 AC: 2609 AN: 8414

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 3309 AN: 14378

East Asian (EAS) AF: 0.0821 AC: 2177 AN: 26532

South Asian (SAS) AF: 0.166 AC: 3240 AN: 19488

European-Finnish (FIN) AF: 0.146 AC: 3085 AN: 21108

Middle Eastern (MID) AF: 0.190 AC: 554 AN: 2914

European-Non Finnish (NFE) AF: 0.200 AC: 183500 AN: 919352

Other (OTH) AF: 0.189 AC: 8264 AN: 43640

GnomAD4 genome AF: 0.205 AC: 31181 AN: 152150 Hom.: 3368 Cov.: 32 AF XY: 0.200 AC XY: 14887 AN XY: 74378

African (AFR) AF: 0.221 AC: 9157 AN: 41492

American (AMR) AF: 0.278 AC: 4252 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3468

East Asian (EAS) AF: 0.0639 AC: 331 AN: 5176

South Asian (SAS) AF: 0.161 AC: 778 AN: 4828

European-Finnish (FIN) AF: 0.137 AC: 1458 AN: 10614

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13689 AN: 67980

Other (OTH) AF: 0.210 AC: 443 AN: 2112

Alfa AF: 0.114 Hom.: 173

Bravo AF: 0.218

Asia WGS AF: 0.114 AC: 398 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.69
PhyloP100		-1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs12971396; hg19: chr19-39737866;