NM_000416.3:c.236A>G

Variant names:

• chr6-137206273-T-C
• rs377227464
• NM_000416.3:c.236A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BS1_Supporting

The NM_000416.3(IFNGR1):​c.236A>G​(p.Asn79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,610,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: IFNGR1 NM_000416.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.840
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000416.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.11210221).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000256 (39/152336) while in subpopulation AFR AF = 0.000577 (24/41576). AF 95% confidence interval is 0.000398. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.236A>G	p.Asn79Ser	missense	Exon 3 of 7	NP_000407.1
	IFNGR1	NM_001363526.1		c.206A>G	p.Asn69Ser	missense	Exon 4 of 8	NP_001350455.1
	IFNGR1	NM_001363527.1		c.113A>G	p.Asn38Ser	missense	Exon 3 of 7	NP_001350456.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.236A>G	p.Asn79Ser	missense	Exon 3 of 7	ENSP00000356713.5
	IFNGR1	ENST00000414770.6	TSL:3	c.206A>G	p.Asn69Ser	missense	Exon 4 of 8	ENSP00000394230.2
	IFNGR1	ENST00000646036.1		c.206A>G	p.Asn69Ser	missense	Exon 4 of 8	ENSP00000496387.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000159 AC: 40 AN: 251174 AF XY: 0.000184

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000134 AC: 195 AN: 1457746 Hom.: 1 Cov.: 28 AF XY: 0.000147 AC XY: 107 AN XY: 725548

African (AFR) AF: 0.000150 AC: 5 AN: 33378

American (AMR) AF: 0.000134 AC: 6 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39650

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000115 AC: 128 AN: 1108276

Other (OTH) AF: 0.000199 AC: 12 AN: 60282

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20 AN XY: 74496

African (AFR) AF: 0.000577 AC: 24 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Immunodeficiency 27A (2)
-	1	-	Disseminated atypical mycobacterial infection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.84
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.32
Sift	Benign	0.094	T
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.72
MPC		0.11
ClinPred		0.028	T
GERP RS		0.43
Varity_R		0.29
gMVP		0.52
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs377227464; hg19: chr6-137527410;