19-39247226-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000634967.1(IFNL4):​c.304G>A​(p.Ala102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000927 in 1,079,306 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: IFNL4 ENST00000634967.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

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>A		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>A	p.Ala102Thr	missense	Exon 4 of 4	ENSP00000489559.1
	IFNL4	ENST00000634680.1	TSL:1	c.232G>A	p.Ala78Thr	missense	Exon 3 of 3	ENSP00000489240.1
	IFNL4	ENST00000606380.2	TSL:1	c.*76G>A		3_prime_UTR	Exon 5 of 5	ENSP00000476098.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.27e-7 AC: 1 AN: 1079306 Hom.: 0 Cov.: 31 AF XY: 0.00000196 AC XY: 1 AN XY: 509540

African (AFR) AF: 0.00 AC: 0 AN: 22880

American (AMR) AF: 0.00 AC: 0 AN: 8420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14382

East Asian (EAS) AF: 0.0000377 AC: 1 AN: 26532

South Asian (SAS) AF: 0.00 AC: 0 AN: 19496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2914

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 919916

Other (OTH) AF: 0.00 AC: 0 AN: 43656

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.7
DANN	Benign	0.85
PhyloP100		-1.2

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: rs12971396; hg19: chr19-39737866;