16-3068006-T-G

Variant names:

• chr16-3068006-T-G
• rs774367638
• NM_001376923.1:c.137T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001376923.1(IL32):​c.137T>G​(p.Leu46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L46V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IL32 NM_001376923.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0750
• Publications: 2 publications found

Genes affected

IL32 (HGNC:16830): (interleukin 32) This gene encodes a member of the cytokine family. The protein contains a tyrosine sulfation site, 3 potential N-myristoylation sites, multiple putative phosphorylation sites, and an RGD cell-attachment sequence. Expression of this protein is increased after the activation of T-cells by mitogens or the activation of NK cells by IL-2. This protein induces the production of TNFalpha from macrophage cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11005297).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376923.1. 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
	IL32	NM_001376923.1	MANE Select	c.137T>G	p.Leu46Arg	missense	Exon 5 of 7	NP_001363852.1	P24001-2
	IL32	NM_001308078.4		c.275T>G	p.Leu92Arg	missense	Exon 4 of 6	NP_001295007.1	P24001-1
	IL32	NM_001369587.3		c.275T>G	p.Leu92Arg	missense	Exon 4 of 6	NP_001356516.1	P24001-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL32	ENST00000525643.7	TSL:1 MANE Select	c.137T>G	p.Leu46Arg	missense	Exon 5 of 7	ENSP00000432218.3	P24001-2
	IL32	ENST00000396890.6	TSL:1	c.275T>G	p.Leu92Arg	missense	Exon 4 of 6	ENSP00000380099.2	P24001-1
	IL32	ENST00000325568.9	TSL:1	c.137T>G	p.Leu46Arg	missense	Exon 5 of 7	ENSP00000324742.5	P24001-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251372 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727218

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000143583), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.075
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.014	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.38		Loss of helix (P = 0.0138)
MVP		0.82
MPC		0.40
ClinPred		0.27	T
GERP RS		0.78
Varity_R		0.36
gMVP		0.014

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs774367638; hg19: chr16-3118007;