19-39244133-C-G

Position:

• chr19-39244133-C-G

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.283G>C​(p.Glu95Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,134 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (14 hom.)
• Consequence: IFNL3 NM_172139.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.599

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=0.006387025).
• BP6: Variant 19-39244133-C-G is Benign according to our data. Variant chr19-39244133-C-G is described in ClinVar as [Benign]. Clinvar id is 710145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00677 (1031/152256) while in subpopulation AFR AF= 0.0239 (994/41544). AF 95% confidence interval is 0.0227. There are 12 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1031 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNL3	NM_172139.4	c.283G>C	p.Glu95Gln	missense_variant	3/5	ENST00000413851.3	NP_742151.2
IFNL3	NM_001346937.2	c.295G>C	p.Glu99Gln	missense_variant	4/6		NP_001333866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL3	ENST00000413851.3	c.283G>C	p.Glu95Gln	missense_variant	3/5	1	NM_172139.4	ENSP00000409000	A2
IFNL3	ENST00000613087.5	c.295G>C	p.Glu99Gln	missense_variant	4/6	1		ENSP00000481633	P4

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1031 AN: 152138 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00182 AC: 458 AN: 251094 Hom.: 5 AF XY: 0.00135 AC XY: 184 AN XY: 135808

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000696 AC: 1017 AN: 1461878 Hom.: 14 Cov.: 33 AF XY: 0.000562 AC XY: 409 AN XY: 727242

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00677 AC: 1031 AN: 152256 Hom.: 12 Cov.: 32 AF XY: 0.00666 AC XY: 496 AN XY: 74450

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00205 Hom.: 4

Bravo AF: 0.00799

ESP6500AA AF: 0.0291 AC: 128

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00237 AC: 288

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	.;T
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.048
Sift	Benign	0.27	.;T
Sift4G	Benign	0.12	T;T
Polyphen		0.98	.;D
Vest4		0.16
MVP		0.21
MPC		0.26
ClinPred		0.0097	T
GERP RS		2.1
Varity_R		0.18
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs147679979; hg19: chr19-39734773;