rs749956849

chr6-137204354-TA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000416.3(IFNGR1):c.523del(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 Conflicting classifications of pathogenicity (no stars). 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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: -0.383

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208588.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1}. Variant chr6-137204354-TA-T is described in Lovd as [Pathogenic]. Variant chr6-137204354-TA-T is described in Lovd as [Pathogenic]. Variant chr6-137204354-TA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR1	NM_000416.3 linkuse as main transcript	c.523del	p.Tyr175MetfsTer2	frameshift_variant	4/7	ENST00000367739.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR1	ENST00000367739.9 linkuse as main transcript	c.523del	p.Tyr175MetfsTer2	frameshift_variant	4/7	1	NM_000416.3	P2	P15260-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251312

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135824

show subpopulations

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 SAS 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:

AN:

1461516

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Disseminated atypical mycobacterial infection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 208588). 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). This variant is present in population databases (rs749956849, gnomAD 0.003%). 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). -

Inherited Immunodeficiency Diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2019

- -

Immunodeficiency 27A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 07, 2014

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. -

Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over