rs9376267

Variant names:

• chr6-137209894-C-T
• rs9376267
• NM_000416.3:c.86-2817G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000416.3(IFNGR1):​c.86-2817G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 398,504 control chromosomes in the GnomAD database, including 13,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4593 hom., cov: 32)
  • Exomes 𝑓: 0.26 (9005 hom.)
• Consequence: IFNGR1 NM_000416.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.151
• Publications: 26 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-137209894-C-T is Benign according to our data. Variant chr6-137209894-C-T is described in ClinVar as [Benign]. Clinvar id is 2688425.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNGR1	NM_000416.3	c.86-2817G>A		intron_variant	Intron 1 of 6	ENST00000367739.9	NP_000407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNGR1	ENST00000367739.9	c.86-2817G>A		intron_variant	Intron 1 of 6	1	NM_000416.3	ENSP00000356713.5

Frequencies

GnomAD3 genomes AF: 0.230 AC: 35035 AN: 152054 Hom.: 4576 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.260 AC: 64120 AN: 246332 Hom.: 9005 Cov.: 0 AF XY: 0.261 AC XY: 32547 AN XY: 124834

African (AFR) AF: 0.151 AC: 1083 AN: 7180

American (AMR) AF: 0.254 AC: 1887 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 2500 AN: 9240

East Asian (EAS) AF: 0.449 AC: 10287 AN: 22894

South Asian (SAS) AF: 0.540 AC: 1638 AN: 3032

European-Finnish (FIN) AF: 0.238 AC: 4957 AN: 20820

Middle Eastern (MID) AF: 0.240 AC: 311 AN: 1294

European-Non Finnish (NFE) AF: 0.235 AC: 37198 AN: 158072

Other (OTH) AF: 0.260 AC: 4259 AN: 16368

GnomAD4 genome AF: 0.231 AC: 35092 AN: 152172 Hom.: 4593 Cov.: 32 AF XY: 0.238 AC XY: 17720 AN XY: 74384

African (AFR) AF: 0.146 AC: 6075 AN: 41524

American (AMR) AF: 0.255 AC: 3898 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 937 AN: 3470

East Asian (EAS) AF: 0.443 AC: 2295 AN: 5184

South Asian (SAS) AF: 0.541 AC: 2600 AN: 4808

European-Finnish (FIN) AF: 0.235 AC: 2485 AN: 10580

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 16013 AN: 68006

Other (OTH) AF: 0.244 AC: 515 AN: 2110

Alfa AF: 0.237 Hom.: 13444

Bravo AF: 0.220

Asia WGS AF: 0.490 AC: 1699 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 45% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.73
PhyloP100		0.15
Mutation Taster		=100/0	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: rs9376267; hg19: chr6-137531031;