Genetic Variant IFNL3:c.259-126T>C (chr19-39244283-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_172139.4(IFNL3):c.259-126T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,480,780 control chromosomes in the GnomAD database, including 59,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.30 ( 6936 hom., cov: 29)

Exomes 𝑓: 0.28 ( 52993 hom. )

Consequence

IFNL3
NM_172139.4 intron

Scores

Clinical Significance

drug response reviewed by expert panel O:3

Conservation

PhyloP100: -0.860

Publications

76 publications found

Variant links:

Genes affected

IFNL3 (HGNC:18365): (interferon lambda 3) This gene encodes a cytokine distantly related to type I interferons and the IL-10 family. This gene, interleukin 28A (IL28A), and interleukin 29 (IL29) are three closely related cytokine genes that form a cytokine gene cluster on a chromosomal region mapped to 19q13. Expression of the cytokines encoded by the three genes can be induced by viral infection. All three cytokines have been shown to interact with a heterodimeric class II cytokine receptor that consists of interleukin 10 receptor, beta (IL10RB) and interleukin 28 receptor, alpha (IL28RA). [provided by RefSeq, Jul 2008]

IFNL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172139.4. 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
	IFNL3	NM_172139.4	MANE Select	c.259-126T>C		intron	N/A	NP_742151.2
	IFNL3	NM_001346937.2		c.271-126T>C		intron	N/A	NP_001333866.1	A0A0C4DGW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNL3	ENST00000413851.3	TSL:1 MANE Select	c.259-126T>C		intron	N/A	ENSP00000409000.2	Q8IZI9
	IFNL3	ENST00000613087.5	TSL:1	c.271-126T>C		intron	N/A	ENSP00000481633.1	A0A0C4DGW8

Frequencies

GnomAD3 genomes

AF:

0.297

AC:

44904

AN:

151146

Hom.:

6925

Cov.:

show subpopulations

Gnomad AFR

AF:

0.327

Gnomad AMI

AF:

0.334

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.389

Gnomad EAS

AF:

0.0710

Gnomad SAS

AF:

0.214

Gnomad FIN

AF:

0.220

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.297

Gnomad OTH

AF:

0.301

GnomAD4 exome

AF:

0.279

AC:

370626

AN:

1329516

Hom.:

52993

Cov.:

AF XY:

0.277

AC XY:

181980

AN XY:

656916

show subpopulations

African (AFR)

AF:

0.324

AC:

9991

AN:

30834

American (AMR)

AF:

0.386

AC:

13776

AN:

35734

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

8439

AN:

22292

East Asian (EAS)

AF:

0.0797

AC:

2992

AN:

37552

South Asian (SAS)

AF:

0.221

AC:

16461

AN:

74454

European-Finnish (FIN)

AF:

0.233

AC:

11249

AN:

48356

Middle Eastern (MID)

AF:

0.303

AC:

1640

AN:

5406

European-Non Finnish (NFE)

AF:

0.285

AC:

290800

AN:

1019344

Other (OTH)

AF:

0.275

AC:

15278

AN:

55544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

13366

26733

40099

53466

66832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9574

19148

28722

38296

47870

<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:

0.297

AC:

44959

AN:

151264

Hom.:

6936

Cov.:

AF XY:

0.291

AC XY:

21496

AN XY:

73894

show subpopulations

African (AFR)

AF:

0.328

AC:

13488

AN:

41176

American (AMR)

AF:

0.344

AC:

5235

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

1349

AN:

3466

East Asian (EAS)

AF:

0.0713

AC:

363

AN:

5090

South Asian (SAS)

AF:

0.214

AC:

1021

AN:

4762

European-Finnish (FIN)

AF:

0.220

AC:

2312

AN:

10494

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.297

AC:

20151

AN:

67754

Other (OTH)

AF:

0.298

AC:

627

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1518

3037

4555

6074

7592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

440

880

1320

1760

2200

<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:

0.303

Hom.:

5559

Bravo

AF:

0.310

Asia WGS

AF:

0.157

AC:

549

AN:

3478

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

peginterferon alfa-2a response - Efficacy (1)

peginterferon alfa-2b response - Efficacy (1)

ribavirin response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.8

(source)

DANN

Benign

0.68

PhyloP100

-0.86

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over