Genetic Variant NM_006850.3:c.538T>G (chr1-206902976-T-G) – 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_006850.3(IL24):c.538T>G(p.Leu180Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,172 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 29 hom. )

Consequence

IL24
NM_006850.3 missense, splice_region

Scores

Splicing: ADA: 0.0001269

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.633

Publications

9 publications found

Variant links:

Genes affected

IL24 (HGNC:11346): (interleukin 24) This gene encodes a member of the IL10 family of cytokines. It was identified as a gene induced during terminal differentiation in melanoma cells. The protein encoded by this gene can induce apoptosis selectively in various cancer cells. Overexpression of this gene leads to elevated expression of several GADD family genes, which correlates with the induction of apoptosis. The phosphorylation of mitogen-activated protein kinase 14 (MAPK7/P38), and heat shock 27kDa protein 1 (HSPB2/HSP27) are found to be induced by this gene in melanoma cells, but not in normal immortal melanocytes. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

IL24 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=0.005724877).

BP6

Variant 1-206902976-T-G is Benign according to our data. Variant chr1-206902976-T-G is described in ClinVar as Benign. ClinVar VariationId is 770860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00196 (298/152312) while in subpopulation EAS AF = 0.0224 (116/5186). AF 95% confidence interval is 0.0191. There are 2 homozygotes in GnomAd4. There are 151 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_006850.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL24	NM_006850.3	MANE Select	c.538T>G	p.Leu180Val	missense splice_region	Exon 7 of 7	NP_006841.1	Q13007-1
IL24	NM_001185156.1		c.541T>G	p.Leu181Val	missense splice_region	Exon 7 of 7	NP_001172085.1	Q13007-2
IL24	NM_001185157.1		c.382T>G	p.Leu128Val	missense splice_region	Exon 6 of 6	NP_001172086.1	Q13007-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL24	ENST00000294984.7	TSL:1 MANE Select	c.538T>G	p.Leu180Val	missense splice_region	Exon 7 of 7	ENSP00000294984.2	Q13007-1
IL24	ENST00000391929.7	TSL:1	c.541T>G	p.Leu181Val	missense splice_region	Exon 7 of 7	ENSP00000375795.3	Q13007-2
IL24	ENST00000367093.3	TSL:1	c.382T>G	p.Leu128Val	missense splice_region	Exon 6 of 6	ENSP00000356060.3	Q13007-3

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

298

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.0223

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00334

AC:

837

AN:

250790

AF XY:

0.00360

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00496

Gnomad EAS exome

AF:

0.0194

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00254

AC:

3715

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

1932

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00520

AC:

136

AN:

26136

East Asian (EAS)

AF:

0.0176

AC:

697

AN:

39698

South Asian (SAS)

AF:

0.00806

AC:

695

AN:

86254

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00174

AC:

1935

AN:

1111992

Other (OTH)

AF:

0.00316

AC:

191

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

189

377

566

754

943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00196

AC:

298

AN:

152312

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41556

American (AMR)

AF:

0.00131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.0224

AC:

116

AN:

5186

South Asian (SAS)

AF:

0.00580

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68016

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00202

Hom.:

Bravo

AF:

0.00164

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00357

AC:

433

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Benign

0.042

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.92

PhyloP100

-0.63

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.23

Sift

Uncertain

0.020

Sift4G

Benign

0.072

Polyphen

0.90

Vest4

0.39

MVP

0.27

MPC

0.30

ClinPred

0.042

GERP RS

-0.76

Varity_R

0.28

gMVP

0.35

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.052

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

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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