19-39244460-C-T

Position:

• chr19-39244460-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.215G>A​(p.Arg72His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,609,538 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (15 hom., cov: 30)
  • Exomes 𝑓: 0.0018 (22 hom.)
• Consequence: IFNL3 NM_172139.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04

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=0.006099552).
• BP6: Variant 19-39244460-C-T is Benign according to our data. Variant chr19-39244460-C-T is described in ClinVar as [Benign]. Clinvar id is 768989.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 = 0.00944 (1435/152064) while in subpopulation AFR AF= 0.027 (1119/41442). AF 95% confidence interval is 0.0257. There are 15 homozygotes in gnomad4. There are 684 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1435 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNL3	NM_172139.4	c.215G>A	p.Arg72His	missense_variant	2/5	ENST00000413851.3	NP_742151.2
IFNL3	NM_001346937.2	c.227G>A	p.Arg76His	missense_variant	3/6		NP_001333866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL3	ENST00000413851.3	c.215G>A	p.Arg72His	missense_variant	2/5	1	NM_172139.4	ENSP00000409000	A2
IFNL3	ENST00000613087.5	c.227G>A	p.Arg76His	missense_variant	3/6	1		ENSP00000481633	P4

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1430 AN: 151946 Hom.: 14 Cov.: 30

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00131 AC: 315 AN: 240302 Hom.: 5 AF XY: 0.00111 AC XY: 145 AN XY: 130674

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00651

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000303

Gnomad OTH exome AF: 0.000856

GnomAD4 exome AF: 0.00180 AC: 2619 AN: 1457474 Hom.: 22 Cov.: 33 AF XY: 0.00169 AC XY: 1224 AN XY: 724942

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.00370

Gnomad4 ASJ exome AF: 0.0310

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000384

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00944 AC: 1435 AN: 152064 Hom.: 15 Cov.: 30 AF XY: 0.00920 AC XY: 684 AN XY: 74328

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00258 Hom.: 2

Bravo AF: 0.0110

ExAC AF: 0.000223 AC: 27

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	0.070
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0062	.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.053	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.0061	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.18	.;N
REVEL	Benign	0.053
Sift	Benign	0.14	.;T
Sift4G	Benign	0.17	T;T
Polyphen		0.90	.;P
Vest4		0.089
MVP		0.18
MPC		0.25
ClinPred		0.0069	T
GERP RS		-3.4
Varity_R		0.071
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201418207; hg19: chr19-39735100; COSMIC: COSV99065571; COSMIC: COSV99065571;