6-137219280-C-A

Variant names:

• chr6-137219280-C-A
• rs11575931
• NM_000416.3:c.48G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000416.3(IFNGR1):​c.48G>T​(p.Arg16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R16R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IFNGR1 NM_000416.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078030854).

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.48G>T	p.Arg16Ser	missense	Exon 1 of 7	NP_000407.1
	IFNGR1	NM_001363526.1		c.-353G>T		upstream_gene	N/A	NP_001350455.1
	IFNGR1	NM_001363527.1		c.-647G>T		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.48G>T	p.Arg16Ser	missense	Exon 1 of 7	ENSP00000356713.5
	IFNGR1	ENST00000458076.6	TSL:3	c.48G>T	p.Arg16Ser	missense	Exon 1 of 7	ENSP00000389249.2
	IFNGR1	ENST00000696695.1		c.48G>T	p.Arg16Ser	missense	Exon 1 of 6	ENSP00000512816.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 244084 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459636 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 725880

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 85654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111238

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.0065	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	2.8
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.093
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.23
Sift	Benign	0.63	T
Sift4G	Benign	0.78	T
Polyphen		0.037	B
Vest4		0.067
MutPred		0.54		Gain of sheet (P = 0.0028)
MVP		0.80
MPC		0.056
ClinPred		0.047	T
GERP RS		1.3
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.10
gMVP		0.64
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11575931; hg19: chr6-137540417;