rs8103142

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172139.4(IFNL3):c.209A>G(p.Lys70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,562,762 control chromosomes in the GnomAD database, including 85,144 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13782 hom., cov: 30)

Exomes 𝑓: 0.30 ( 71362 hom. )

Consequence

IFNL3
NM_172139.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.52

Publications

105 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.3711763E-5).

BP6

Variant 19-39244466-T-C is Benign according to our data. Variant chr19-39244466-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 511091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNL3	NM_172139.4 link	c.209A>G	p.Lys70Arg	missense_variant	Exon 2 of 5	ENST00000413851.3	NP_742151.2	Q8IZI9A0A7R8C2Z6
IFNL3	NM_001346937.2 link	c.221A>G	p.Lys74Arg	missense_variant	Exon 3 of 6		NP_001333866.1	Q8IZI9A0A0C4DGW8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNL3	ENST00000413851.3 link	c.209A>G	p.Lys70Arg	missense_variant	Exon 2 of 5	1	NM_172139.4	ENSP00000409000.2		Q8IZI9
IFNL3	ENST00000613087.5 link	c.221A>G	p.Lys74Arg	missense_variant	Exon 3 of 6	1		ENSP00000481633.1		A0A0C4DGW8

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60034

AN:

151586

Hom.:

13742

Cov.:

show subpopulations

Gnomad AFR

AF:

0.628

Gnomad AMI

AF:

0.370

Gnomad AMR

AF:

0.382

Gnomad ASJ

AF:

0.428

Gnomad EAS

AF:

0.0718

Gnomad SAS

AF:

0.231

Gnomad FIN

AF:

0.240

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.378

GnomAD2 exomes

AF:

0.289

AC:

65750

AN:

227246

AF XY:

0.279

show subpopulations

Gnomad AFR exome

AF:

0.597

Gnomad AMR exome

AF:

0.395

Gnomad ASJ exome

AF:

0.376

Gnomad EAS exome

AF:

0.0578

Gnomad FIN exome

AF:

0.227

Gnomad NFE exome

AF:

0.283

Gnomad OTH exome

AF:

0.308

GnomAD4 exome

AF:

0.300

AC:

423987

AN:

1411058

Hom.:

71362

Cov.:

AF XY:

0.297

AC XY:

208467

AN XY:

701368

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.638

AC:

20544

AN:

32212

American (AMR)

AF:

0.406

AC:

17197

AN:

42382

Ashkenazi Jewish (ASJ)

AF:

0.417

AC:

10519

AN:

25218

East Asian (EAS)

AF:

0.0784

AC:

3095

AN:

39496

South Asian (SAS)

AF:

0.233

AC:

19704

AN:

84396

European-Finnish (FIN)

AF:

0.249

AC:

13108

AN:

52686

Middle Eastern (MID)

AF:

0.323

AC:

1773

AN:

5492

European-Non Finnish (NFE)

AF:

0.299

AC:

320123

AN:

1070504

Other (OTH)

AF:

0.305

AC:

17924

AN:

58672

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.369

Heterozygous variant carriers

12444

24888

37333

49777

62221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10246

20492

30738

40984

51230

<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:

0.396

AC:

60121

AN:

151704

Hom.:

13782

Cov.:

AF XY:

0.387

AC XY:

28678

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.629

AC:

25974

AN:

41306

American (AMR)

AF:

0.382

AC:

5822

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.428

AC:

1486

AN:

3468

East Asian (EAS)

AF:

0.0722

AC:

371

AN:

5142

South Asian (SAS)

AF:

0.231

AC:

1107

AN:

4796

European-Finnish (FIN)

AF:

0.240

AC:

2534

AN:

10560

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.318

AC:

21590

AN:

67876

Other (OTH)

AF:

0.374

AC:

787

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1646

3292

4939

6585

8231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

532

1064

1596

2128

2660

<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:

0.346

Hom.:

4943

Bravo

AF:

0.418

ExAC

AF:

0.291

AC:

35285

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 09, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.066

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.0028

.;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.00055

LIST_S2

Benign

0.10

T;T

MetaRNN

Benign

0.000044

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.7

.;N

PhyloP100

-1.5

PrimateAI

Benign

0.29

PROVEAN

Benign

0.32

.;N

REVEL

Benign

0.0050

Sift

Benign

1.0

.;T

Sift4G

Benign

0.66

T;T

Polyphen

0.0

.;B

Vest4

0.022

MPC

0.16

ClinPred

0.0012

GERP RS

-3.1

Varity_R

0.084

gMVP

0.067

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over