rs17175322

Positions:

chr6-137206982-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PM1PM5BP4_StrongBP6_Very_StrongBS1

The NM_000416.3(IFNGR1):c.181G>A(p.Val61Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,607,632 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V61E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

IFNGR1
NM_000416.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.54

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:

IFNGR1 (HGNC:):

IFNGR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PM1

In a strand (size 7) in uniprot entity INGR1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000416.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-137206981-A-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.008826196).

BP6

Variant 6-137206982-C-T is Benign according to our data. Variant chr6-137206982-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 531675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-137206982-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00251 (382/152224) while in subpopulation AFR AF= 0.00874 (363/41548). AF 95% confidence interval is 0.008. There are 1 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNGR1	NM_000416.3 linkuse as main transcript	c.181G>A	p.Val61Ile	missense_variant	2/7	ENST00000367739.9	NP_000407.1	P15260-1A0A0S2Z3Y2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNGR1	ENST00000367739.9 linkuse as main transcript	c.181G>A	p.Val61Ile	missense_variant	2/7	1	NM_000416.3	ENSP00000356713.5		P15260-1

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

383

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00876

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000752

AC:

189

AN:

251294

Hom.:

AF XY:

0.000537

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00941

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000383

AC:

558

AN:

1455408

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

257

AN XY:

724402

show subpopulations

Gnomad4 AFR exome

AF:

0.00861

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.000498

GnomAD4 genome

AF:

0.00251

AC:

382

AN:

152224

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00874

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000603

Hom.:

Bravo

AF:

0.00306

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000923

AC:

112

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Disseminated atypical mycobacterial infection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

IFNGR1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Immunodeficiency 27A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.51

D;.;.;.;.;.;.;T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.63

T;.;T;.;.;T;T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.0088

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.87

N;.;.;.;.;.;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.075

T;.;.;.;.;.;.;T;T

Sift4G

Uncertain

0.045

D;.;.;.;.;.;.;.;.

Polyphen

1.0

D;.;.;.;.;.;.;.;.

Vest4

0.46

MVP

0.73

MPC

0.21

ClinPred

0.029

GERP RS

4.8

Varity_R

0.17

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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