19-39243712-C-T

Position:

• chr19-39243712-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172139.4(IFNL3):​c.511G>A​(p.Glu171Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,610,250 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (10 hom., cov: 32)
  • Exomes 𝑓: 0.017 (198 hom.)
• Consequence: IFNL3 NM_172139.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.120

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=0.0044042766).
• BP6: Variant 19-39243712-C-T is Benign according to our data. Variant chr19-39243712-C-T is described in ClinVar as [Benign]. Clinvar id is 770465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1821/152282) while in subpopulation NFE AF= 0.0194 (1319/68020). AF 95% confidence interval is 0.0185. There are 10 homozygotes in gnomad4. There are 844 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1821 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNL3	NM_172139.4	c.511G>A	p.Glu171Lys	missense_variant	5/5	ENST00000413851.3	NP_742151.2
IFNL3	NM_001346937.2	c.523G>A	p.Glu175Lys	missense_variant	6/6		NP_001333866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL3	ENST00000413851.3	c.511G>A	p.Glu171Lys	missense_variant	5/5	1	NM_172139.4	ENSP00000409000	A2
IFNL3	ENST00000613087.5	c.523G>A	p.Glu175Lys	missense_variant	6/6	1		ENSP00000481633	P4

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1821 AN: 152164 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.0125 AC: 2853 AN: 227868 Hom.: 23 AF XY: 0.0126 AC XY: 1558 AN XY: 123496

Gnomad AFR exome AF: 0.00292

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00647

Gnomad EAS exome AF: 0.000537

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0183

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0169 AC: 24584 AN: 1457968 Hom.: 198 Cov.: 33 AF XY: 0.0166 AC XY: 12030 AN XY: 725098

Gnomad4 AFR exome AF: 0.00228

Gnomad4 AMR exome AF: 0.00515

Gnomad4 ASJ exome AF: 0.00622

Gnomad4 EAS exome AF: 0.000379

Gnomad4 SAS exome AF: 0.00975

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0194

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0120 AC: 1821 AN: 152282 Hom.: 10 Cov.: 32 AF XY: 0.0113 AC XY: 844 AN XY: 74458

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.0206

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0166 Hom.: 8

Bravo AF: 0.0101

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0148 AC: 127

ExAC AF: 0.0114 AC: 1383

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	.;T
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	2.0	.;M
MutationTaster	Benign	0.81	D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	.;D
REVEL	Benign	0.11
Sift	Benign	0.062	.;T
Sift4G	Uncertain	0.054	T;T
Polyphen		1.0	.;D
Vest4		0.061
MPC		0.41
ClinPred		0.025	T
GERP RS		1.6
Varity_R		0.18
gMVP		0.33

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

Other links and lift over

dbSNP: rs62120527; hg19: chr19-39734352; COSMIC: COSV69830174; COSMIC: COSV69830174;