12-68158261-TAAAAAAAA-TAAAAA

Variant names:

• chr12-68158261-TAAA-T
• rs2234686
• NM_000619.3:c.115-5_115-3delTTT

Variant summary

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

The NM_000619.3(IFNG):​c.115-5_115-3delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,199,252 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IFNG NM_000619.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.416
• Publications: 9 publications found

Genes affected

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000619.3. 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
	IFNG	NM_000619.3	MANE Select	c.115-5_115-3delTTT		splice_region intron	N/A	NP_000610.2	P01579

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNG	ENST00000229135.4	TSL:1 MANE Select	c.115-5_115-3delTTT		splice_region intron	N/A	ENSP00000229135.3	P01579
	IFNG-AS1	ENST00000536914.1	TSL:5	n.337-76267_337-76265delAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147296 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00146 AC: 206 AN: 140762 AF XY: 0.00134

Gnomad AFR exome AF: 0.00227

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000916

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000939

GnomAD4 exome AF: 0.000648 AC: 777 AN: 1199252 Hom.: 0 AF XY: 0.000673 AC XY: 402 AN XY: 597404

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

African (AFR) AF: 0.00115 AC: 28 AN: 24358

American (AMR) AF: 0.00129 AC: 36 AN: 27856

Ashkenazi Jewish (ASJ) AF: 0.000819 AC: 17 AN: 20768

East Asian (EAS) AF: 0.000418 AC: 15 AN: 35922

South Asian (SAS) AF: 0.00180 AC: 114 AN: 63386

European-Finnish (FIN) AF: 0.000595 AC: 26 AN: 43718

Middle Eastern (MID) AF: 0.000214 AC: 1 AN: 4668

European-Non Finnish (NFE) AF: 0.000552 AC: 513 AN: 928930

Other (OTH) AF: 0.000544 AC: 27 AN: 49646

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 147296 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 71642

African (AFR) AF: 0.00 AC: 0 AN: 40092

American (AMR) AF: 0.00 AC: 0 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.00 AC: 0 AN: 4702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66626

Other (OTH) AF: 0.00 AC: 0 AN: 2022

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42

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

Other links and lift over

dbSNP: rs2234686; hg19: chr12-68552041;