6-137219383-A-G

Variant names:

• chr6-137219383-A-G
• rs2234711
• NM_000416.3:c.-56T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 94 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• immunodeficiency 27A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 355565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000416.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	NM_000416.3	MANE Select	c.-56T>C		5_prime_UTR	Exon 1 of 7	NP_000407.1
	IFNGR1	NM_001363526.1		c.-456T>C		upstream_gene	N/A	NP_001350455.1
	IFNGR1	NM_001363527.1		c.-750T>C		upstream_gene	N/A	NP_001350456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.-56T>C		5_prime_UTR	Exon 1 of 7	ENSP00000356713.5
	IFNGR1	ENST00000478333.1	TSL:2	n.67T>C		non_coding_transcript_exon	Exon 1 of 2
	IFNGR1	ENST00000414770.6	TSL:3	c.-197T>C		5_prime_UTR	Exon 1 of 8	ENSP00000394230.2

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

African (AFR) AF: 0.516 AC: 16724 AN: 32418

American (AMR) AF: 0.368 AC: 13338 AN: 36290

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12482 AN: 25196

East Asian (EAS) AF: 0.540 AC: 19953 AN: 36946

South Asian (SAS) AF: 0.605 AC: 48455 AN: 80096

European-Finnish (FIN) AF: 0.366 AC: 18129 AN: 49528

Middle Eastern (MID) AF: 0.508 AC: 2851 AN: 5614

European-Non Finnish (NFE) AF: 0.384 AC: 416287 AN: 1085168

Other (OTH) AF: 0.438 AC: 25569 AN: 58414

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

African (AFR) AF: 0.506 AC: 21008 AN: 41508

American (AMR) AF: 0.394 AC: 6032 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1738 AN: 3470

East Asian (EAS) AF: 0.577 AC: 2975 AN: 5156

South Asian (SAS) AF: 0.628 AC: 3031 AN: 4824

European-Finnish (FIN) AF: 0.353 AC: 3740 AN: 10580

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.387 AC: 26279 AN: 67972

Other (OTH) AF: 0.472 AC: 995 AN: 2108

Alfa AF: 0.643 Hom.: 8010

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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mycobacterium tuberculosis, protection against Benign:1

Jun 01, 2009

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

Immunodeficiency 27A Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 01, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Hepatitis B virus, susceptibility to Other:1

Jun 01, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.6
DANN	Benign	0.57
PhyloP100		0.090
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2234711; hg19: chr6-137540520; COSMIC: COSV62990213; COSMIC: COSV62990213;