chr19-39296503-A-G

Position:

• chr19-39296503-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172140.2(IFNL1):​c.82A>G​(p.Thr28Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,613,572 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (52 hom.)
• Consequence: IFNL1 NM_172140.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24

Genes affected

IFNL1 (HGNC:18363): (interferon lambda 1) This gene encodes a cytokine distantly related to type I interferons and the IL-10 family. This gene, interleukin 28A (IL28A), and interleukin 28B (IL28B) 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=0.0027097166).
• BP6: Variant 19-39296503-A-G is Benign according to our data. Variant chr19-39296503-A-G is described in ClinVar as [Benign]. Clinvar id is 716504.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 = 0.0128 (1944/152248) while in subpopulation AFR AF= 0.0429 (1782/41546). AF 95% confidence interval is 0.0412. There are 38 homozygotes in gnomad4. There are 930 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNL1	NM_172140.2	c.82A>G	p.Thr28Ala	missense_variant	1/5	ENST00000333625.3	NP_742152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNL1	ENST00000333625.3	c.82A>G	p.Thr28Ala	missense_variant	1/5	1	NM_172140.2	ENSP00000329991.1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1940 AN: 152130 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00378 AC: 950 AN: 251280 Hom.: 22 AF XY: 0.00272 AC XY: 369 AN XY: 135816

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00163 AC: 2378 AN: 1461324 Hom.: 52 Cov.: 31 AF XY: 0.00141 AC XY: 1022 AN XY: 726940

Gnomad4 AFR exome AF: 0.0462

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.0128 AC: 1944 AN: 152248 Hom.: 38 Cov.: 31 AF XY: 0.0125 AC XY: 930 AN XY: 74452

Gnomad4 AFR AF: 0.0429

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00284 Hom.: 11

Bravo AF: 0.0153

ESP6500AA AF: 0.0404 AC: 178

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00422 AC: 512

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000771

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	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.54
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.021
Sift	Benign	0.65	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.048
MPC		0.071
ClinPred		0.0018	T
GERP RS		-0.27
Varity_R		0.025
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs114823100; hg19: chr19-39787143;