1-206769830-T-C

Variant names:

• chr1-206769830-T-C
• rs1490806720
• NM_000572.3:c.443A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000572.3(IL10):​c.443A>G​(p.Lys148Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL10 NM_000572.3 missense, splice_region
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

Genes affected

IL10 (HGNC:5962): (interleukin 10) The protein encoded by this gene is a cytokine produced primarily by monocytes and to a lesser extent by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. Mutations in this gene are associated with an increased susceptibility to HIV-1 infection and rheumatoid arthritis. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL10	NM_000572.3	c.443A>G	p.Lys148Arg	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000423557.1	NP_000563.1
IL10	NM_001382624.1	c.188A>G	p.Lys63Arg	missense_variant, splice_region_variant	Exon 2 of 3		NP_001369553.1
IL10	NR_168466.1	n.740A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6
IL10	NR_168467.1	n.270A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL10	ENST00000423557.1	c.443A>G	p.Lys148Arg	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_000572.3	ENSP00000412237.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inflammatory bowel disease Uncertain:1

Jun 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with IL10-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 148 of the IL10 protein (p.Lys148Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.50
Sift	Benign	0.051	T;.
Sift4G	Benign	0.10	T;.
Polyphen		0.99	D;.
Vest4		0.23
MutPred		0.60		Loss of methylation at K148 (P = 0.0098);.;
MVP		0.90
MPC		0.35
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.54
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.79		Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1490806720; hg19: chr1-206943175;