rs587776856

chr6-137200919-GATTA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000416.3(IFNGR1):c.819_822del(p.Asn274HisfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 6 pathogenic variants in the truncated region.
• PP5: Variant 6-137200919-GATTA-G is Pathogenic according to our data. Variant chr6-137200919-GATTA-G is described in ClinVar as [Pathogenic]. Clinvar id is 17947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-137200919-GATTA-G is described in Lovd as [Pathogenic]. Variant chr6-137200919-GATTA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR1	NM_000416.3	c.819_822del	p.Asn274HisfsTer2	frameshift_variant	6/7	ENST00000367739.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR1	ENST00000367739.9	c.819_822del	p.Asn274HisfsTer2	frameshift_variant	6/7	1	NM_000416.3	P2

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

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10192386). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift deletion p.N274Hfs*2 in IFNGR1 (NM_000416.3) has been reported previously reported in the heterozygous state in multiple individuals with recurrent mycobacterial infections, sometimes following BCG vaccination (Glosli et al, 2008). The p.N274Hfs*2 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 2 residues until a stop codon is reached. For these reasons, this variant has been classified as Pathogenic -

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 07, 2022

- -

Disseminated atypical mycobacterial infection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This sequence change creates a premature translational stop signal (p.Asn274Hisfs*2) in the IFNGR1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 216 amino acid(s) of the IFNGR1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant Mendelian susceptibility to mycobacterial infection (PMID: 10192386, 18171304). It has also been observed to segregate with disease in related individuals. This variant is also known as 818del4. ClinVar contains an entry for this variant (Variation ID: 17947). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects IFNGR1 function (PMID: 20015550). For these reasons, this variant has been classified as Pathogenic. -

IFN-gamma receptor 1 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 19, 2017

Variant summary: The IFNGR1 c.819_822delTAAT (p.Asn274Hisfs) variant results in a premature termination codon, predicted to cause a truncated or absent IFNGR1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 94886 control chromosomes. The variant was reported in multiple affected individuals and families in the literature in the heterozyous state, suggesting an autosomal dominant inheritance pattern. 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. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2016

The c.819_822delTAAT pathogenic variant in the IFNGR1 gene has been reported previously in the heterozygous state in multiple individuals with osteolytic lesions and recurrent mycobacterial infections, sometimes following BCG vaccination (Jouanguy et al., 1999; Edgar et al., 2001; Glosli et al., 2008; Takeda et al., 2014). The c.819_822delTAAT variant causes a frameshift starting with codon Asparagine 274, changes this amino acid to a Histidine residue, ultimately replacing 216 amino acids with one incorrect amino acid and creates a premature Stop codon at position 2 of the new reading frame, which is denoted p.Asn274HisfsX2. 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). The c.819_822delTAAT variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.819_822delTAAT as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776856; hg19: chr6-137522056;