19-39243681-A-C

Variant names:

• chr19-39243681-A-C
• NM_172139.4:c.542T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_172139.4(IFNL3):​c.542T>G​(p.Leu181Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L181F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFNL3 NM_172139.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46
• Publications: 0 publications found

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]

ENSG00000296032 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

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.542T>G	p.Leu181Arg	missense	Exon 5 of 5	NP_742151.2
	IFNL3	NM_001346937.2		c.554T>G	p.Leu185Arg	missense	Exon 6 of 6	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.542T>G	p.Leu181Arg	missense	Exon 5 of 5	ENSP00000409000.2	Q8IZI9
	IFNL3	ENST00000613087.5	TSL:1	c.554T>G	p.Leu185Arg	missense	Exon 6 of 6	ENSP00000481633.1	A0A0C4DGW8
	ENSG00000296032	ENST00000735578.1		n.*156A>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.061
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.68		Loss of stability (P = 0.0055)
MVP		0.36
MPC		0.94
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.90
gMVP		0.60
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

hg19: chr19-39734321;