rs3799488

Variant names:

• chr6-137198643-T-C
• rs3799488
• NM_000416.3:c.862-4A>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.862-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,605,704 control chromosomes in the GnomAD database, including 12,087 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (919 hom., cov: 31)
  • Exomes 𝑓: 0.12 (11168 hom.)
• Consequence: IFNGR1 NM_000416.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003753
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00900

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=-0.81).
• BP6: Variant 6-137198643-T-C is Benign according to our data. Variant chr6-137198643-T-C is described in ClinVar as [Benign]. Clinvar id is 355555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-137198643-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNGR1	NM_000416.3	c.862-4A>G		splice_region_variant, intron_variant	Intron 6 of 6	ENST00000367739.9	NP_000407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNGR1	ENST00000367739.9	c.862-4A>G		splice_region_variant, intron_variant	Intron 6 of 6	1	NM_000416.3	ENSP00000356713.5

Frequencies

GnomAD3 genomes AF: 0.0945 AC: 14349 AN: 151898 Hom.: 915 Cov.: 31

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0994

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.0845

GnomAD3 exomes AF: 0.119 AC: 29206 AN: 245934 Hom.: 2035 AF XY: 0.119 AC XY: 15952 AN XY: 133630

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.259

Gnomad SAS exome AF: 0.0981

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.118 AC: 171430 AN: 1453688 Hom.: 11168 Cov.: 30 AF XY: 0.117 AC XY: 84901 AN XY: 723620

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.0986

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.0945 AC: 14361 AN: 152016 Hom.: 919 Cov.: 31 AF XY: 0.0949 AC XY: 7053 AN XY: 74304

Gnomad4 AFR AF: 0.0206

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0994

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.0831

Alfa AF: 0.114 Hom.: 1765

Bravo AF: 0.0919

Asia WGS AF: 0.145 AC: 505 AN: 3478

EpiCase AF: 0.111

EpiControl AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

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

- -

Immunodeficiency 27A Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0
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: rs3799488; hg19: chr6-137519780; COSMIC: COSV62989865; COSMIC: COSV62989865;