rs2069709

Variant names:

• chr12-68159923-C-A
• rs2069709
• ENST00000536914.1:n.337-74606C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The ENST00000536914.1(IFNG-AS1):​n.337-74606C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 152,262 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.0069 (11 hom., cov: 31)
• Consequence: IFNG-AS1 ENST00000536914.1 intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.404
• Publications: 37 publications found

Genes affected

IFNG-AS1 (HGNC:43910): (IFNG antisense RNA 1)

IFNG (HGNC:5438): (interferon gamma) This gene encodes a soluble cytokine that is a member of the type II interferon class. The encoded protein is secreted by cells of both the innate and adaptive immune systems. The active protein is a homodimer that binds to the interferon gamma receptor which triggers a cellular response to viral and microbial infections. Mutations in this gene are associated with an increased susceptibility to viral, bacterial and parasitic infections and to several autoimmune diseases. [provided by RefSeq, Dec 2015]

IFNG Gene-Disease associations (from GenCC):

• immunodeficiency 69

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP5: Variant 12-68159923-C-A is Pathogenic according to our data. Variant chr12-68159923-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14724.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00692 (1053/152262) while in subpopulation AFR AF = 0.0241 (1000/41534). AF 95% confidence interval is 0.0228. There are 11 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 11 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000536914.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNG	NM_000619.3	MANE Select	c.-308G>T		upstream_gene	N/A	NP_000610.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNG-AS1	ENST00000536914.1	TSL:5	n.337-74606C>A		intron	N/A
	IFNG	ENST00000229135.4	TSL:1 MANE Select	c.-308G>T		upstream_gene	N/A	ENSP00000229135.3

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1051 AN: 152144 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00384

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00692 AC: 1053 AN: 152262 Hom.: 11 Cov.: 31 AF XY: 0.00665 AC XY: 495 AN XY: 74462

African (AFR) AF: 0.0241 AC: 1000 AN: 41534

American (AMR) AF: 0.00235 AC: 36 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00980 Hom.: 4

Bravo AF: 0.00790

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Acquired immunodeficiency syndrome, rapid progression to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.79
PhyloP100		0.40
PromoterAI		-0.0022	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2069709; hg19: chr12-68553703;