rs387906593

Positions:

• chr6-137219326-A-C
• chr6-137219326-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_000416.3(IFNGR1):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IFNGR1 NM_000416.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.29

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000416.3 (IFNGR1) was described as [Pathogenic] in ClinVar as 29607
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR1	NM_000416.3	c.2T>G	p.Met1?	start_lost	1/7	ENST00000367739.9
IFNGR1	XM_011535793.3	c.-140T>G		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR1	ENST00000367739.9	c.2T>G	p.Met1?	start_lost	1/7	1	NM_000416.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000860 AC: 2 AN: 232430 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125730

Gnomad AFR exome AF: 0.0000696

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000955

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453900 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 722414

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.78		Loss of sheet (P = 0.0011);Loss of sheet (P = 0.0011);
MVP		0.98
ClinPred		0.90	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.97
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs387906593; hg19: chr6-137540463;