19-39248513-CT-C

Variant names:

• chr19-39248513-CT-C
• rs11322783
• ENST00000634967.1:c.66delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000634967.1(IFNL4):​c.66delA​(p.Gly23AlafsTer110) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (13877 hom., cov: 0)
  • Exomes 𝑓: 0.31 (53187 hom.)
• Consequence: IFNL4 ENST00000634967.1 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 28 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.629 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNL4	NR_074079.1		n.343delA		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNL4	ENST00000634967.1	TSL:1	c.66delA	p.Gly23AlafsTer110	frameshift	Exon 1 of 4	ENSP00000489559.1
	IFNL4	ENST00000606380.2	TSL:1	c.66delA	p.Gly23AlafsTer158	frameshift	Exon 1 of 5	ENSP00000476098.2	K9M1I6
	IFNL4	ENST00000634680.1	TSL:1	c.66delA	p.Gly23AlafsTer86	frameshift	Exon 1 of 3	ENSP00000489240.1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60151 AN: 151764 Hom.: 13844 Cov.: 0

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.0683

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.376

GnomAD2 exomes AF: 0.222 AC: 4 AN: 18 AF XY: 0.125

Gnomad AFR exome AF: 0.500

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.306 AC: 330720 AN: 1079170 Hom.: 53187 Cov.: 0 AF XY: 0.306 AC XY: 156109 AN XY: 509462

African (AFR) AF: 0.649 AC: 14892 AN: 22948

American (AMR) AF: 0.403 AC: 3391 AN: 8412

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 5576 AN: 14376

East Asian (EAS) AF: 0.0867 AC: 2298 AN: 26516

South Asian (SAS) AF: 0.242 AC: 4718 AN: 19484

European-Finnish (FIN) AF: 0.260 AC: 5488 AN: 21104

Middle Eastern (MID) AF: 0.320 AC: 933 AN: 2914

European-Non Finnish (NFE) AF: 0.304 AC: 280064 AN: 919770

Other (OTH) AF: 0.306 AC: 13360 AN: 43646

GnomAD4 genome AF: 0.397 AC: 60233 AN: 151882 Hom.: 13877 Cov.: 0 AF XY: 0.387 AC XY: 28714 AN XY: 74234

African (AFR) AF: 0.636 AC: 26275 AN: 41332

American (AMR) AF: 0.379 AC: 5788 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1363 AN: 3466

East Asian (EAS) AF: 0.0686 AC: 355 AN: 5172

South Asian (SAS) AF: 0.234 AC: 1128 AN: 4822

European-Finnish (FIN) AF: 0.240 AC: 2542 AN: 10586

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21556 AN: 67920

Other (OTH) AF: 0.372 AC: 785 AN: 2108

Alfa AF: 0.377 Hom.: 1434

Bravo AF: 0.420

Asia WGS AF: 0.199 AC: 696 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11322783; hg19: chr19-39739153; COSMIC: COSV69830124; COSMIC: COSV69830124;