3-159995428-G-A

Position:

• chr3-159995428-G-A

Variant summary

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

The NM_000882.4(IL12A):​c.631G>A​(p.Val211Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,606,752 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (24 hom.)
• Consequence: IL12A NM_000882.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.438

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004370719).
• BP6: Variant 3-159995428-G-A is Benign according to our data. Variant chr3-159995428-G-A is described in ClinVar as [Benign]. Clinvar id is 708885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0093 (1416/152282) while in subpopulation AFR AF= 0.0263 (1091/41542). AF 95% confidence interval is 0.025. There are 22 homozygotes in gnomad4. There are 679 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12A	NM_000882.4	c.631G>A	p.Val211Met	missense_variant	7/7		NP_000873.2
IL12A	NM_001354582.2	c.589G>A	p.Val197Met	missense_variant	6/6		NP_001341511.1
IL12A	NM_001397992.1	c.529G>A	p.Val177Met	missense_variant	7/7		NP_001384921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12A	ENST00000699704.1	c.529G>A	p.Val177Met	missense_variant	7/7			ENSP00000514529.1

Frequencies

GnomAD3 genomes AF: 0.00932 AC: 1418 AN: 152164 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00352 AC: 860 AN: 244252 Hom.: 8 AF XY: 0.00298 AC XY: 394 AN XY: 132098

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.00415

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000593

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00374

GnomAD4 exome AF: 0.00218 AC: 3174 AN: 1454470 Hom.: 24 Cov.: 29 AF XY: 0.00209 AC XY: 1512 AN XY: 723356

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000604

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00492

GnomAD4 genome AF: 0.00930 AC: 1416 AN: 152282 Hom.: 22 Cov.: 32 AF XY: 0.00912 AC XY: 679 AN XY: 74470

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00335 Hom.: 3

Bravo AF: 0.0106

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00351 AC: 426

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	IL12A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.053	.;T;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.072
MVP		0.41
MPC		0.99
ClinPred		0.014	T
GERP RS		3.1
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs35990253; hg19: chr3-159713215;