3-159995456-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000882.4(IL12A):c.659C>T(p.Pro220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,607,448 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P220P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: IL12A NM_000882.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.454

Genes affected

IL12A (HGNC:5969): (interleukin 12A) This gene encodes a subunit of a cytokine that acts on T and natural killer cells, and has a broad array of biological activities. The cytokine is a disulfide-linked heterodimer composed of the 35-kD subunit encoded by this gene, and a 40-kD subunit that is a member of the cytokine receptor family. This cytokine is required for the T-cell-independent induction of interferon (IFN)-gamma, and is important for the differentiation of both Th1 and Th2 cells. The responses of lymphocytes to this cytokine are mediated by the activator of transcription protein STAT4. Nitric oxide synthase 2A (NOS2A/NOS2) is found to be required for the signaling process of this cytokine in innate immunity. [provided by RefSeq, Jul 2008]

IL12A-AS1 (HGNC:49094): (IL12A antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057649314).
• BP6: Variant 3-159995456-C-T is Benign according to our data. Variant chr3-159995456-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 713905.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12A	NM_001397992.1	c.557C>T	p.Pro186Leu	missense_variant	7/7	ENST00000699704.1
IL12A	NM_000882.4	c.659C>T	p.Pro220Leu	missense_variant	7/7
IL12A-AS1	NR_108088.1	n.1085-1151G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12A	ENST00000699704.1	c.557C>T	p.Pro186Leu	missense_variant	7/7		NM_001397992.1	P1
IL12A-AS1	ENST00000497452.5	n.1085-1151G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000761 AC: 187 AN: 245812 Hom.: 1 AF XY: 0.000715 AC XY: 95 AN XY: 132912

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000399

Gnomad ASJ exome AF: 0.00469

Gnomad EAS exome AF: 0.00282

Gnomad SAS exome AF: 0.000137

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000604

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000739 AC: 1075 AN: 1455144 Hom.: 2 Cov.: 29 AF XY: 0.000716 AC XY: 518 AN XY: 723836

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000252

Gnomad4 ASJ exome AF: 0.00453

Gnomad4 EAS exome AF: 0.00369

Gnomad4 SAS exome AF: 0.000142

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000669

Gnomad4 OTH exome AF: 0.000682

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74474

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.000691

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000675 AC: 82

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	1.1
Dann	Benign	0.74
DEOGEN2	Benign	0.056	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0088	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.11
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0040	B;.;.
Vest4		0.068
MVP		0.16
MPC		0.35
ClinPred		0.012	T
GERP RS		-3.8
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs55691228; hg19: chr3-159713243; COSMIC: COSV99975758; COSMIC: COSV99975758;