NM_000416.3:c.523delT

Variant names:

• chr6-137204354-TA-T
• rs749956849
• NM_000416.3:c.523delT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000416.3(IFNGR1):​c.523delT​(p.Tyr175MetfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: IFNGR1 NM_000416.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.383
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• immunodeficiency 27A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-137204354-TA-T is Pathogenic according to our data. Variant chr6-137204354-TA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 208588.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	NM_000416.3	MANE Select	c.523delT	p.Tyr175MetfsTer2	frameshift	Exon 4 of 7	NP_000407.1
	IFNGR1	NM_001363526.1		c.493delT	p.Tyr165MetfsTer2	frameshift	Exon 5 of 8	NP_001350455.1
	IFNGR1	NM_001363527.1		c.400delT	p.Tyr134MetfsTer2	frameshift	Exon 4 of 7	NP_001350456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.523delT	p.Tyr175MetfsTer2	frameshift	Exon 4 of 7	ENSP00000356713.5
	IFNGR1	ENST00000414770.6	TSL:3	c.493delT	p.Tyr165MetfsTer2	frameshift	Exon 5 of 8	ENSP00000394230.2
	IFNGR1	ENST00000646036.1		c.493delT	p.Tyr165MetfsTer2	frameshift	Exon 5 of 8	ENSP00000496387.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251312 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461516 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111718

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 01, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IFNGR1 p.Y175Mfs*2 variant has been reported as a homozygous or compound heterozygous variant in 6 cases of mycobacterial infection susceptibility due to interferon gamma receptor deficiency (Khanolkar_2018_ PMID: 28927822; Olbrich_2015_PMID:26173802; Koscielniak_2003_PMID:12712974; Dorman_2004_PMID:15589309; Marazzi_2009_PMID:19880337). The variant was identified in dbSNP (ID: rs749956849) and ClinVar (classified as pathogenic by Invitae and Laboratory for Molecular Medicine). The variant was identified in control databases in 4 of 251312 chromosomes at a frequency of 0.00001592 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 4 of 113632 chromosomes (freq: 0.000035), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.523del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 175 and leads to a premature stop codon 2 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the IFNGR1 gene are an established mechanism of disease in mycobacteriosis immunodeficiency and is the type of variant expected to cause the disorder. Further, functional data from a patient homozygous for this variant demonstrated a lack of interferon gamma receptor expression at the cell surface (Koscielniak_2003_PMID:12712974). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

Disseminated atypical mycobacterial infection Pathogenic:1

Jun 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr175Metfs*2) in the IFNGR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IFNGR1 are known to be pathogenic (PMID: 8960473, 9806040). This variant is present in population databases (rs749956849, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Mendelian susceptibility to mycobacterial disease (MSMD) due to interferon-gamma receptor 1 deficiency (PMID: 15589309, 19880337, 25216720). ClinVar contains an entry for this variant (Variation ID: 208588). For these reasons, this variant has been classified as Pathogenic.

Inherited Immunodeficiency Diseases Pathogenic:1

Jan 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Immunodeficiency 27A Pathogenic:1

Oct 07, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr175MetfsX2 variant in IFNGR1 has been reported in 4 homozygous individuals with IFNGR1 deficiency (Koscielnak 2003, Dorman 2004, Marazzi 2010) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 175 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In vivo functional studies indicate this variant results in the absence of surface IFNGR1 expression and diminished cellular response to interferon gamma (Koscielnak 2003). In summary, this variant meets our criteria to be classified as pathogenic for IFNGR1 deficiency in an autosomal recessive manner (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/) due to the predicted impact to the protein and functional data.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.38
Mutation Taster		=2/198	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: rs749956849; hg19: chr6-137525491;