rs2234711

Positions:

• chr6-137219383-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.-56T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,561,786 control chromosomes in the GnomAD database, including 134,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14831 hom., cov: 33)
  • Exomes 𝑓: 0.41 (120067 hom.)
• Consequence: IFNGR1 NM_000416.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: 0.0900

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-137219383-A-G is Benign according to our data. Variant chr6-137219383-A-G is described in ClinVar as [Benign]. Clinvar id is 355565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-137219383-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.-56T>C		5_prime_UTR_variant	1/7	ENST00000367739.9	NP_000407.1
IFNGR1	XM_011535793.3	c.-197T>C		5_prime_UTR_variant	1/8		XP_011534095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNGR1	ENST00000367739.9	c.-56T>C		5_prime_UTR_variant	1/7	1	NM_000416.3	ENSP00000356713	P2

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66223 AN: 151998 Hom.: 14787 Cov.: 33

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.470

GnomAD4 exome AF: 0.407 AC: 573788 AN: 1409670 Hom.: 120067 Cov.: 41 AF XY: 0.413 AC XY: 287672 AN XY: 696240

Gnomad4 AFR exome AF: 0.516

Gnomad4 AMR exome AF: 0.368

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.540

Gnomad4 SAS exome AF: 0.605

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.384

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.436 AC: 66326 AN: 152116 Hom.: 14831 Cov.: 33 AF XY: 0.439 AC XY: 32676 AN XY: 74364

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.577

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.387

Gnomad4 OTH AF: 0.472

Alfa AF: 0.409 Hom.: 1563

Bravo AF: 0.435

Asia WGS AF: 0.631 AC: 2191 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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. -

Disseminated atypical mycobacterial infection Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Mycobacterium tuberculosis, protection against Benign:1

protective, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Immunodeficiency 27A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Helicobacter pylori infection, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Hepatitis B virus, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.6
DANN	Benign	0.57
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: rs2234711; hg19: chr6-137540520; COSMIC: COSV62990213; COSMIC: COSV62990213;