rs17181471

chr6-137219286-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000416.3(IFNGR1):c.42G>A(p.Val14=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00966 in 1,611,826 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (3 hom., cov: 33)
  • Exomes 𝑓: 0.010 (111 hom.)
• Consequence: IFNGR1 NM_000416.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.669

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 6-137219286-C-T is Benign according to our data. Variant chr6-137219286-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.669 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0061 (930/152356) while in subpopulation NFE AF= 0.0105 (715/68028). AF 95% confidence interval is 0.00987. There are 3 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR1	NM_000416.3	c.42G>A	p.Val14=	synonymous_variant	1/7	ENST00000367739.9
IFNGR1	XM_011535793.3	c.-100G>A		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR1	ENST00000367739.9	c.42G>A	p.Val14=	synonymous_variant	1/7	1	NM_000416.3	P2

Frequencies

GnomAD3 genomes AF: 0.00611 AC: 930 AN: 152238 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00593 AC: 1446 AN: 243840 Hom.: 8 AF XY: 0.00587 AC XY: 776 AN XY: 132188

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00284

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.00168

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.0100 AC: 14634 AN: 1459470 Hom.: 111 Cov.: 40 AF XY: 0.00982 AC XY: 7129 AN XY: 725788

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.00304

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00226

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00774

GnomAD4 genome AF: 0.00610 AC: 930 AN: 152356 Hom.: 3 Cov.: 33 AF XY: 0.00581 AC XY: 433 AN XY: 74496

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00966 Hom.: 14

Bravo AF: 0.00659

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Disseminated atypical mycobacterial infection Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Interferon gamma receptor deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing;curation

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

Aug 18, 2011

- -

IFNGR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

IFNGR1: BP4, BP7, BS1, BS2 -

Immunodeficiency 27A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	6.9
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17181471; hg19: chr6-137540423;