Genetic Variant NM_001558.4:c.697G>A (chr11-117995597-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001558.4(IL10RA):c.697G>A(p.Val233Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,162 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V233G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0044 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 7 hom. )

Consequence

IL10RA
NM_001558.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.34

Publications

7 publications found

Variant links:

Genes affected

IL10RA (HGNC:5964): (interleukin 10 receptor subunit alpha) The protein encoded by this gene is a receptor for interleukin 10. This protein is structurally related to interferon receptors. It has been shown to mediate the immunosuppressive signal of interleukin 10, and thus inhibits the synthesis of proinflammatory cytokines. This receptor is reported to promote survival of progenitor myeloid cells through the insulin receptor substrate-2/PI 3-kinase/AKT pathway. Activation of this receptor leads to tyrosine phosphorylation of JAK1 and TYK2 kinases. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Jan 2009]

IL10RA Gene-Disease associations (from GenCC):

inflammatory bowel disease 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
IL10-related early-onset inflammatory bowel disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IL10RA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009112895).

BP6

Variant 11-117995597-G-A is Benign according to our data. Variant chr11-117995597-G-A is described in ClinVar as Benign. ClinVar VariationId is 538062.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 = 0.00435 (663/152298) while in subpopulation AFR AF = 0.0127 (528/41556). AF 95% confidence interval is 0.0118. There are 2 homozygotes in GnomAd4. There are 304 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001558.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL10RA	NM_001558.4	MANE Select	c.697G>A	p.Val233Met	missense	Exon 6 of 7	NP_001549.2
IL10RA	NM_001440423.1		c.250G>A	p.Val84Met	missense	Exon 4 of 5	NP_001427352.1
IL10RA	NR_026691.2		n.901G>A		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL10RA	ENST00000227752.8	TSL:1 MANE Select	c.697G>A	p.Val233Met	missense	Exon 6 of 7	ENSP00000227752.4
IL10RA	ENST00000529924.6	TSL:1	n.2275G>A		non_coding_transcript_exon	Exon 5 of 6
IL10RA	ENST00000951964.1		c.691G>A	p.Val231Met	missense	Exon 6 of 7	ENSP00000622023.1

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

661

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0127

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00439

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00181

AC:

455

AN:

251466

AF XY:

0.00159

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00745

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000316

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000917

AC:

1341

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000843

AC XY:

613

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0131

AC:

437

AN:

33480

American (AMR)

AF:

0.00217

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00879

AC:

349

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000297

AC:

330

AN:

1112008

Other (OTH)

AF:

0.00182

AC:

110

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

154

230

307

384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00435

AC:

663

AN:

152298

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

304

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0127

AC:

528

AN:

41556

American (AMR)

AF:

0.00438

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00578

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68032

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00565

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inflammatory bowel disease 28 (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0091

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

1.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

REVEL

Benign

0.22

Sift

Uncertain

0.014

Sift4G

Uncertain

0.014

Polyphen

0.99

Vest4

0.21

MVP

0.38

MPC

0.32

ClinPred

0.010

GERP RS

3.3

Varity_R

0.052

gMVP

0.61

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over