6-137219233-A-G

Position:

• chr6-137219233-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000416.3(IFNGR1):​c.85+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,602,902 control chromosomes in the GnomAD database, including 138,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14807 hom., cov: 32)
  • Exomes 𝑓: 0.41 (123435 hom.)
• Consequence: IFNGR1 NM_000416.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.0250

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-137219233-A-G is Benign according to our data. Variant chr6-137219233-A-G is described in ClinVar as [Benign]. Clinvar id is 355562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-137219233-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNGR1	NM_000416.3	c.85+10T>C		intron_variant		ENST00000367739.9	NP_000407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNGR1	ENST00000367739.9	c.85+10T>C		intron_variant		1	NM_000416.3	ENSP00000356713.5

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66181 AN: 151938 Hom.: 14762 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.469

GnomAD3 exomes AF: 0.431 AC: 98680 AN: 229126 Hom.: 22266 AF XY: 0.440 AC XY: 54697 AN XY: 124220

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.500

Gnomad EAS exome AF: 0.577

Gnomad SAS exome AF: 0.602

Gnomad FIN exome AF: 0.362

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.407 AC: 590179 AN: 1450846 Hom.: 123435 Cov.: 41 AF XY: 0.413 AC XY: 297737 AN XY: 720686

Gnomad4 AFR exome AF: 0.516

Gnomad4 AMR exome AF: 0.359

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.541

Gnomad4 SAS exome AF: 0.605

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.436

GnomAD4 genome AF: 0.436 AC: 66286 AN: 152056 Hom.: 14807 Cov.: 32 AF XY: 0.439 AC XY: 32657 AN XY: 74342

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.577

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.471

Alfa AF: 0.393 Hom.: 10975

Bravo AF: 0.435

Asia WGS AF: 0.631 AC: 2191 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 56. Only high quality variants are reported. -

Immunodeficiency 27A Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Disseminated atypical mycobacterial infection Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.5
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs7749390; hg19: chr6-137540370;