19-39244133-C-T

Variant names:

• chr19-39244133-C-T
• rs147679979
• NM_172139.4:c.283G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172139.4(IFNL3):​c.283G>A​(p.Glu95Lys) 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 benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E95Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFNL3 NM_172139.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.599
• Publications: 1 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2220217).

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.283G>A	p.Glu95Lys	missense	Exon 3 of 5	NP_742151.2
	IFNL3	NM_001346937.2		c.295G>A	p.Glu99Lys	missense	Exon 4 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.283G>A	p.Glu95Lys	missense	Exon 3 of 5	ENSP00000409000.2	Q8IZI9
	IFNL3	ENST00000613087.5	TSL:1	c.295G>A	p.Glu99Lys	missense	Exon 4 of 6	ENSP00000481633.1	A0A0C4DGW8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251094 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Benign	0.048
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.60
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.14
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.27
MutPred		0.29		Gain of ubiquitination at E95 (P = 0.0258)
MVP		0.33
MPC		0.34
ClinPred		0.81	D
GERP RS		2.1
Varity_R		0.24
gMVP		0.40
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs147679979; hg19: chr19-39734773;