chr1-206769849-C-G

Position:

• chr1-206769849-C-G

Variant summary

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

The NM_000572.3(IL10):​c.424G>C​(p.Val142Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IL10 NM_000572.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

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/exons	MANE	Protein	UniProt
IL10	NM_000572.3	c.424G>C	p.Val142Leu	missense_variant	4/5	ENST00000423557.1	NP_000563.1
IL10	NM_001382624.1	c.169G>C	p.Val57Leu	missense_variant	2/3		NP_001369553.1
IL10	NR_168466.1	n.721G>C		non_coding_transcript_exon_variant	5/6
IL10	NR_168467.1	n.251G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL10	ENST00000423557.1	c.424G>C	p.Val142Leu	missense_variant	4/5	1	NM_000572.3	ENSP00000412237	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inflammatory bowel disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2023

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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1715483). 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 valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 142 of the IL10 protein (p.Val142Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.73	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.27	N;.
REVEL	Benign	0.28
Sift	Benign	0.069	T;.
Sift4G	Uncertain	0.014	D;.
Polyphen		0.18	B;.
Vest4		0.28
MutPred		0.81		Loss of methylation at K143 (P = 0.0389);.;
MVP		0.83
MPC		0.30
ClinPred		0.51	D
GERP RS		4.2
Varity_R		0.18
gMVP		0.38

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: rs1674768626; hg19: chr1-206943194;