12-68158261-TAAAAAAAA-TAAAAAA

Variant names:

• chr12-68158261-TAA-T
• rs2234686
• NM_000619.3:c.115-4_115-3delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000619.3(IFNG):​c.115-4_115-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,210,686 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: IFNG NM_000619.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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.

• PM2: Variant has high frequency in the SAS (0.192) population. However there is too low homozygotes in high coverage region: (expected more than 2531, got 0).
• BP6: Variant 12-68158261-TAA-T is Benign according to our data. Variant chr12-68158261-TAA-T is described in ClinVar as Benign. ClinVar VariationId is 1282751.Status of the report is criteria_provided_single_submitter, 1 stars.

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.115-4_115-3delTT		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.115-4_115-3delTT		splice_region intron	N/A	ENSP00000229135.3	P01579
	IFNG-AS1	ENST00000536914.1	TSL:5	n.337-76267_337-76266delAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 194 AN: 147022 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00155

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.000790

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.00624

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00111

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.152 AC: 21421 AN: 140762 AF XY: 0.157

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.0911

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.104 AC: 110518 AN: 1063588 Hom.: 0 AF XY: 0.107 AC XY: 56624 AN XY: 528492

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

African (AFR) AF: 0.172 AC: 3367 AN: 19556

American (AMR) AF: 0.139 AC: 3439 AN: 24670

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 2543 AN: 17270

East Asian (EAS) AF: 0.0727 AC: 2330 AN: 32038

South Asian (SAS) AF: 0.195 AC: 10908 AN: 56042

European-Finnish (FIN) AF: 0.0849 AC: 3307 AN: 38974

Middle Eastern (MID) AF: 0.125 AC: 488 AN: 3902

European-Non Finnish (NFE) AF: 0.0956 AC: 79172 AN: 828518

Other (OTH) AF: 0.116 AC: 4964 AN: 42618

⚠️ 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 AF: 0.00132 AC: 194 AN: 147098 Hom.: 0 Cov.: 0 AF XY: 0.00148 AC XY: 106 AN XY: 71592

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

African (AFR) AF: 0.000698 AC: 28 AN: 40138

American (AMR) AF: 0.00155 AC: 23 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3424

East Asian (EAS) AF: 0.000791 AC: 4 AN: 5054

South Asian (SAS) AF: 0.000426 AC: 2 AN: 4690

European-Finnish (FIN) AF: 0.00624 AC: 58 AN: 9290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00111 AC: 74 AN: 66464

Other (OTH) AF: 0.00196 AC: 4 AN: 2038

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1361

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV57490625;