Genetic Variant IFNL4:p.Ala31Thr (chr19-39248489-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000634967.1(IFNL4):c.91G>A(p.Ala31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,079,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IFNL4
ENST00000634967.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.35

Publications

0 publications found

Variant links:

Genes affected

IFNL4 (HGNC:44480): (interferon lambda 4 (gene/pseudogene)) This gene is a polymorphic pseudogene which, in some humans, encodes the interferon (IFN) lambda 4 protein. Humans are polymorphic for the dinucleotide TT/deltaG allele. Compared to the ancestral state in non-human primates, the TT allele produces a frameshift in the coding region of this gene which is predicted to induce nonsense-mediated mRNA decay. This allele, and an allele in the first intron of this gene, have experienced a rapid increase in frequency and show indications of positive selection. The ancestral states of these alleles are associated with an impaired ability to clear hepatitis C virus. This gene, like other type III interferons (IFNs), interacts with the IFN lambda receptor complex (IFNLR) whose signaling is generally restricted to epithelial cells. This gene resides in a cluster of four type III IFN genes and at least two pseudogenes on chromosome 19q13.2. In general, interferons are produced in response to viral infection and block viral replication and propagation to uninfected cells by activating the JAK-STAT pathway and up-regulating antiviral genes. Multiple alternatively spliced transcripts have been described for this gene but their biological validity and protein coding status is still being ascertained. [provided by RefSeq, May 2017]

IFNL4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05993831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNL4	NR_074079.1 link	n.368G>A		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
IFNL4	ENST00000634967.1 link	c.91G>A	p.Ala31Thr	missense_variant	Exon 1 of 4	1	ENSP00000489559.1
IFNL4	ENST00000606380.2 link	c.91G>A	p.Ala31Thr	missense_variant	Exon 1 of 5	1	ENSP00000476098.2	K9M1I6
IFNL4	ENST00000634680.1 link	c.91G>A	p.Ala31Thr	missense_variant	Exon 1 of 3	1	ENSP00000489240.1

Frequencies

GnomAD3 genomes

AF:

0.00000672

AC:

AN:

148892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1079284

Hom.:

Cov.:

AF XY:

0.00000196

AC XY:

AN XY:

509536

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22950

American (AMR)

AF:

0.00

AC:

AN:

8414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14374

East Asian (EAS)

AF:

0.00

AC:

AN:

26514

South Asian (SAS)

AF:

0.0000513

AC:

AN:

19496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2914

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

919864

Other (OTH)

AF:

0.0000458

AC:

AN:

43652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000671

AC:

AN:

149004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72816

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38736

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67748

Other (OTH)

AF:

0.00

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0090

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.015

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.27

MetaRNN

Benign

0.060

PhyloP100

-5.4

Vest4

0.068

MVP

0.19

GERP RS

-5.7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over