rs1042155

chr3-159995537-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000882.4(IL12A):c.740T>C(p.Met247Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IL12A NM_000882.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12A	NM_001397992.1	c.638T>C	p.Met213Thr	missense_variant	7/7	ENST00000699704.1
IL12A	NM_000882.4	c.740T>C	p.Met247Thr	missense_variant	7/7
IL12A-AS1	NR_108088.1	n.1085-1232A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12A	ENST00000699704.1	c.638T>C	p.Met213Thr	missense_variant	7/7		NM_001397992.1	P1
IL12A-AS1	ENST00000497452.5	n.1085-1232A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448696 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720480

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.050	D
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.45
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.66
MutPred		0.83		Gain of disorder (P = 0.0716);.;.;
MVP		0.57
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs1042155; hg19: chr3-159713324; COSMIC: COSV59760039; COSMIC: COSV59760039;