rs1887415

Positions:

• chr6-137198101-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000416.3(IFNGR1):​c.1400T>C​(p.Leu467Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,614,140 control chromosomes in the GnomAD database, including 3,621 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (244 hom., cov: 32)
  • Exomes 𝑓: 0.021 (3377 hom.)
• Consequence: IFNGR1 NM_000416.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.394

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009924144).
• BP6: Variant 6-137198101-A-G is Benign according to our data. Variant chr6-137198101-A-G is described in ClinVar as [Benign]. Clinvar id is 355552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-137198101-A-G is described in Lovd as [Likely_benign]. Variant chr6-137198101-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR1	NM_000416.3	c.1400T>C	p.Leu467Pro	missense_variant	7/7	ENST00000367739.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR1	ENST00000367739.9	c.1400T>C	p.Leu467Pro	missense_variant	7/7	1	NM_000416.3	P2

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3143 AN: 152166 Hom.: 238 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.0443

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0512 AC: 12858 AN: 251306 Hom.: 1328 AF XY: 0.0593 AC XY: 8052 AN XY: 135830

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.0846

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.0466

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0214 AC: 31215 AN: 1461856 Hom.: 3377 Cov.: 31 AF XY: 0.0280 AC XY: 20347 AN XY: 727230

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.0787

Gnomad4 ASJ exome AF: 0.00559

Gnomad4 EAS exome AF: 0.0353

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.0198

Gnomad4 NFE exome AF: 0.000762

Gnomad4 OTH exome AF: 0.0285

GnomAD4 genome AF: 0.0208 AC: 3167 AN: 152284 Hom.: 244 Cov.: 32 AF XY: 0.0263 AC XY: 1961 AN XY: 74460

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.0378

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.0448

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.0229

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.0299

Alfa AF: 0.00689 Hom.: 139

Bravo AF: 0.0160

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0518 AC: 6288

Asia WGS AF: 0.215 AC: 745 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Disseminated atypical mycobacterial infection Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Immunodeficiency 27A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.8
DANN	Benign	0.93
DEOGEN2	Benign	0.34	T;.;.;.;.;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.52	T;.;T;.;.;T;T
MetaRNN	Benign	0.0099	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.3	D;.;.;.;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.12	T;.;.;.;.;.;.
Sift4G	Benign	0.10	T;.;.;.;.;.;.
Polyphen		0.26	B;.;.;.;.;.;.
Vest4		0.10
MPC		0.11
ClinPred		0.021	T
GERP RS		2.0
Varity_R		0.65
gMVP		0.52

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: rs1887415; hg19: chr6-137519238; COSMIC: COSV62992036;