1-206902976-T-G

Position:

• chr1-206902976-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/21 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL24	NM_006850.3	c.538T>G	p.Leu180Val	missense_variant, splice_region_variant	7/7	ENST00000294984.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL24	ENST00000294984.7	c.538T>G	p.Leu180Val	missense_variant, splice_region_variant	7/7	1	NM_006850.3	P4

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 298 AN: 152194 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00334 AC: 837 AN: 250790 Hom.: 8 AF XY: 0.00360 AC XY: 488 AN XY: 135622

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 SAS exome AF: 0.00725

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.: 29 Cov.: 33 AF XY: 0.00266 AC XY: 1932 AN XY: 727234

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.0176

Gnomad4 SAS exome AF: 0.00806

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74480

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.0224

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00202 Hom.: 3

Bravo AF: 0.00164

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00357 AC: 433

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;T;.
Eigen	Benign	0.042
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.64	T;T;T
MetaRNN	Benign	0.0057	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.59	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.020	D;D;D
Sift4G	Benign	0.072	T;T;T
Polyphen		0.90	.;P;.
Vest4		0.39
MVP		0.27
MPC		0.30
ClinPred		0.042	T
GERP RS		-0.76
Varity_R		0.28
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs150080259; hg19: chr1-207076321;