Genetic Variant IFNL4:p.Gly23AlafsTer110 (chr19-39248513-CT-C) – ACMG Classification: Benign (-8 pts)

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Variant links:

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]

IFNL4 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNL4	NR_074079.1 link	n.343delA		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
IFNL4	ENST00000634967.1 link	c.66delA	p.Gly23AlafsTer110	frameshift_variant	Exon 1 of 4	1	ENSP00000489559.1
IFNL4	ENST00000606380.2 link	c.66delA	p.Gly23AlafsTer158	frameshift_variant	Exon 1 of 5	1	ENSP00000476098.2	K9M1I6
IFNL4	ENST00000634680.1 link	c.66delA	p.Gly23AlafsTer86	frameshift_variant	Exon 1 of 3	1	ENSP00000489240.1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60151

AN:

151764

Hom.:

13844

Cov.:

show subpopulations

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:

AN:

AF XY:

0.125

show subpopulations

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.:

AF XY:

0.306

AC XY:

156109

AN XY:

509462

show subpopulations

Gnomad4 AFR exome

AF:

0.649

AC:

14892

AN:

22948

Gnomad4 AMR exome

AF:

0.403

AC:

3391

AN:

8412

Gnomad4 ASJ exome

AF:

0.388

AC:

5576

AN:

14376

Gnomad4 EAS exome

AF:

0.0867

AC:

2298

AN:

26516

Gnomad4 SAS exome

AF:

0.242

AC:

4718

AN:

19484

Gnomad4 FIN exome

AF:

0.260

AC:

5488

AN:

21104

Gnomad4 NFE exome

AF:

0.304

AC:

280064

AN:

919770

Gnomad4 Remaining exome

AF:

0.306

AC:

13360

AN:

43646

Heterozygous variant carriers

15422

30845

46267

61690

77112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

10648

21296

31944

42592

53240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.397

AC:

60233

AN:

151882

Hom.:

13877

Cov.:

AF XY:

0.387

AC XY:

28714

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.636

AC:

0.635706

AN:

0.635706

Gnomad4 AMR

AF:

0.379

AC:

0.378796

AN:

0.378796

Gnomad4 ASJ

AF:

0.393

AC:

0.393249

AN:

0.393249

Gnomad4 EAS

AF:

0.0686

AC:

0.0686388

AN:

0.0686388

Gnomad4 SAS

AF:

0.234

AC:

0.233928

AN:

0.233928

Gnomad4 FIN

AF:

0.240

AC:

0.240128

AN:

0.240128

Gnomad4 NFE

AF:

0.317

AC:

0.317373

AN:

0.317373

Gnomad4 OTH

AF:

0.372

AC:

0.372391

AN:

0.372391

Heterozygous variant carriers

1693

3386

5079

6772

8465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

530

1060

1590

2120

2650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

19-39248513-CTT-CT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over