chr6-137198630-C-A

Position:

• chr6-137198630-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000416.3(IFNGR1):​c.871G>T​(p.Val291Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IFNGR1 NM_000416.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.707

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR1	NM_000416.3	c.871G>T	p.Val291Leu	missense_variant	7/7	ENST00000367739.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR1	ENST00000367739.9	c.871G>T	p.Val291Leu	missense_variant	7/7	1	NM_000416.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458284 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Disseminated atypical mycobacterial infection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2017

This variant has not been reported in the literature in individuals with IFNGR1-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 291 of the IFNGR1 protein (p.Val291Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;.;.;.;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.72	T;.;T;.;.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.
MutationTaster	Benign	0.52	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;.;.;.;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.012	D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.
Polyphen		0.98	D;.;.;.;.;.;.
Vest4		0.24
MutPred		0.81		Loss of sheet (P = 0.0181);.;.;.;.;.;.;
MVP		0.92
MPC		0.32
ClinPred		0.82	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554226264; hg19: chr6-137519767;