rs145922845

Variant names:

• chr1-206772393-C-T
• rs145922845
• NM_000572.3:c.43G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-206772393-C-T
• chr1-206772393-C-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000572.3(IL10):​c.43G>A​(p.Gly15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,614,206 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: IL10 NM_000572.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.178
• Publications: 14 publications found

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]

IL19 (HGNC:5990): (interleukin 19) The protein encoded by this gene is a cytokine that belongs to the IL10 cytokine subfamily. This cytokine is found to be preferentially expressed in monocytes. It can bind the IL20 receptor complex and lead to the activation of the signal transducer and activator of transcription 3 (STAT3). A similar cytokine in mouse is reported to up-regulate the expression of IL6 and TNF-alpha and induce apoptosis, which suggests a role of this cytokine in inflammatory responses. Alternatively spliced transcript variants encoding the distinct isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010133684).
• BP6: Variant 1-206772393-C-T is Benign according to our data. Variant chr1-206772393-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456662.
• BS2: High Homozygotes in GnomAdExome4 at 11 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000572.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10	NM_000572.3	MANE Select	c.43G>A	p.Gly15Arg	missense	Exon 1 of 5	NP_000563.1	P22301
	IL19	NM_153758.5	MANE Select	c.-149+1315C>T		intron	N/A	NP_715639.2	Q9UHD0-1
	IL19	NM_001393490.1		c.-149+1563C>T		intron	N/A	NP_001380419.1	Q9UHD0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10	ENST00000423557.1	TSL:1 MANE Select	c.43G>A	p.Gly15Arg	missense	Exon 1 of 5	ENSP00000412237.1	P22301
	IL19	ENST00000659997.3	MANE Select	c.-149+1315C>T		intron	N/A	ENSP00000499459.2	Q9UHD0-1
	IL10	ENST00000659642.2		c.-75G>A		5_prime_UTR	Exon 2 of 6	ENSP00000499509.1	A0A590UK12

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00188 AC: 473 AN: 251274 AF XY: 0.00192

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00319 AC: 4662 AN: 1461858 Hom.: 11 Cov.: 31 AF XY: 0.00310 AC XY: 2258 AN XY: 727228

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000475 AC: 41 AN: 86258

European-Finnish (FIN) AF: 0.00110 AC: 59 AN: 53406

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00395 AC: 4393 AN: 1111996

Other (OTH) AF: 0.00187 AC: 113 AN: 60394

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.00170 AC XY: 127 AN XY: 74502

African (AFR) AF: 0.000505 AC: 21 AN: 41574

American (AMR) AF: 0.00150 AC: 23 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00313 AC: 213 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00274 Hom.: 2

Bravo AF: 0.00193

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00189 AC: 229

EpiCase AF: 0.00267

EpiControl AF: 0.00255

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	Inflammatory bowel disease (1)
-	1	-	Rheumatoid arthritis;C1836230:Susceptibility to HIV infection;C3280677:Graft-versus-host disease, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.18
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Benign	0.34	T
Sift4G	Benign	0.31	T
Polyphen		0.023	B
Vest4		0.40
MutPred		0.79		Gain of methylation at G15 (P = 0.0122)
MVP		0.75
MPC		0.29
ClinPred		0.0095	T
GERP RS		1.7
PromoterAI		-0.023	Neutral
Varity_R		0.093
gMVP		0.52
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs145922845; hg19: chr1-206945738; COSMIC: COSV65594408;