rs8103142

Positions:

• chr19-39244466-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (13782 hom., cov: 30)
  • Exomes 𝑓: 0.30 (71362 hom.)
• Consequence: IFNL3 NM_172139.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.52

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
IFNL3	NM_172139.4	c.209A>G	p.Lys70Arg	missense_variant	2/5	ENST00000413851.3	NP_742151.2
IFNL3	NM_001346937.2	c.221A>G	p.Lys74Arg	missense_variant	3/6		NP_001333866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL3	ENST00000413851.3	c.209A>G	p.Lys70Arg	missense_variant	2/5	1	NM_172139.4	ENSP00000409000	A2
IFNL3	ENST00000613087.5	c.221A>G	p.Lys74Arg	missense_variant	3/6	1		ENSP00000481633	P4

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60034 AN: 151586 Hom.: 13742 Cov.: 30

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

GnomAD3 exomes AF: 0.289 AC: 65750 AN: 227246 Hom.: 11485 AF XY: 0.279 AC XY: 34364 AN XY: 123294

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 SAS exome AF: 0.216

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.: 36 AF XY: 0.297 AC XY: 208467 AN XY: 701368

Gnomad4 AFR exome AF: 0.638

Gnomad4 AMR exome AF: 0.406

Gnomad4 ASJ exome AF: 0.417

Gnomad4 EAS exome AF: 0.0784

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.396 AC: 60121 AN: 151704 Hom.: 13782 Cov.: 30 AF XY: 0.387 AC XY: 28678 AN XY: 74092

Gnomad4 AFR AF: 0.629

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.0722

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.374

Alfa AF: 0.349 Hom.: 3300

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

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

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

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.066
DANN	Benign	0.53
DEOGEN2	Benign	0.0028	.;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.00055	N
LIST_S2	Benign	0.10	T;T
MetaRNN	Benign	0.000044	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.7	.;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
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	T
GERP RS		-3.1
Varity_R		0.084
gMVP		0.067

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

LitVar

Other links and lift over

dbSNP: rs8103142; hg19: chr19-39735106; COSMIC: COSV69829810; COSMIC: COSV69829810;