rs587776856

Variant names:

• chr6-137200919-GATTA-G
• rs587776856
• NM_000416.3:c.819_822delTAAT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_000416.3(IFNGR1):​c.819_822delTAAT​(p.Asn274HisfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329864: This variant produces a truncated protein, lacking the recycling receptor and intracellular domains, which expression studies have shown is increased in patient cells, accumulating on the cell surface thereby impairing cellular IFNv response through a dominant negative effect (Jouanguy et al., 1999" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFNGR1 NM_000416.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.502
• Publications: 10 publications found

Genes affected

IFNGR1 (HGNC:5439): (interferon gamma receptor 1) This gene (IFNGR1) encodes the ligand-binding chain (alpha) of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. A genetic variation in IFNGR1 is associated with susceptibility to Helicobacter pylori infection. In addition, defects in IFNGR1 are a cause of mendelian susceptibility to mycobacterial disease, also known as familial disseminated atypical mycobacterial infection. [provided by RefSeq, Jul 2008]

IFNGR1 Gene-Disease associations (from GenCC):

• autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• immunodeficiency 27A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329864: This variant produces a truncated protein, lacking the recycling receptor and intracellular domains, which expression studies have shown is increased in patient cells, accumulating on the cell surface thereby impairing cellular IFNv response through a dominant negative effect (Jouanguy et al., 1999; van de Wetering et al., 2010).; SCV000696695: "Additionally, in one study the variant resulted in an overall defect in STAT translocation (a downstream function of signaling through the IFNGR) in a patient's cells (Jouanguy_1999), supporting the pathogenic role of the variant."; SCV001380450: Experimental studies have shown that this premature translational stop signal affects IFNGR1 function (PMID: 20015550).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-137200919-GATTA-G is Pathogenic according to our data. Variant chr6-137200919-GATTA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 17947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000416.3. 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
	IFNGR1	NM_000416.3	MANE Select	c.819_822delTAAT	p.Asn274HisfsTer2	frameshift	Exon 6 of 7	NP_000407.1	A0A0S2Z3Y2
	IFNGR1	NM_001363526.1		c.789_792delTAAT	p.Asn264HisfsTer2	frameshift	Exon 7 of 8	NP_001350455.1	A0A2R8Y4U4
	IFNGR1	NM_001363527.1		c.696_699delTAAT	p.Asn233HisfsTer2	frameshift	Exon 6 of 7	NP_001350456.1	A0A2R8YFL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.819_822delTAAT	p.Asn274HisfsTer2	frameshift	Exon 6 of 7	ENSP00000356713.5	P15260-1
	IFNGR1	ENST00000957752.1		c.813_816delTAAT	p.Asn272HisfsTer2	frameshift	Exon 6 of 7	ENSP00000627811.1
	IFNGR1	ENST00000414770.6	TSL:3	c.789_792delTAAT	p.Asn264HisfsTer2	frameshift	Exon 7 of 8	ENSP00000394230.2	A0A2R8Y4U4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency (3)
1	-	-	Disseminated atypical mycobacterial infection (1)
1	-	-	IFN-gamma receptor 1 deficiency (1)
1	-	-	Mycobacterium tuberculosis, susceptibility to;C1838332:Helicobacter pylori infection, susceptibility to;C1864880:Hepatitis B virus, susceptibility to;C4011949:Immunodeficiency 27A;C4014863:Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.50
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs587776856; hg19: chr6-137522056;