6-137198101-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L467L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 244 hom., cov: 32)

Exomes 𝑓: 0.021 ( 3377 hom. )

Consequence

IFNGR1
NM_000416.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.394

Publications

32 publications found

Variant links:

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

IFNGR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 355552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IFNGR1	NM_000416.3	MANE Select	c.1400T>C	p.Leu467Pro	missense	Exon 7 of 7	NP_000407.1
IFNGR1	NM_001363526.1		c.1370T>C	p.Leu457Pro	missense	Exon 8 of 8	NP_001350455.1
IFNGR1	NM_001363527.1		c.1277T>C	p.Leu426Pro	missense	Exon 7 of 7	NP_001350456.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.1400T>C	p.Leu467Pro	missense	Exon 7 of 7	ENSP00000356713.5
IFNGR1	ENST00000957752.1		c.1394T>C	p.Leu465Pro	missense	Exon 7 of 7	ENSP00000627811.1
IFNGR1	ENST00000414770.6	TSL:3	c.1370T>C	p.Leu457Pro	missense	Exon 8 of 8	ENSP00000394230.2

Frequencies

GnomAD3 genomes

AF:

0.0207

AC:

3143

AN:

152166

Hom.:

238

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0512

AC:

12858

AN:

251306

AF XY:

0.0593

show subpopulations

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 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.:

AF XY:

0.0280

AC XY:

20347

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0129

AC:

433

AN:

33478

American (AMR)

AF:

0.0787

AC:

3521

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00559

AC:

146

AN:

26132

East Asian (EAS)

AF:

0.0353

AC:

1402

AN:

39696

South Asian (SAS)

AF:

0.255

AC:

21992

AN:

86258

European-Finnish (FIN)

AF:

0.0198

AC:

1060

AN:

53416

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000762

AC:

847

AN:

1111996

Other (OTH)

AF:

0.0285

AC:

1722

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1646

3292

4939

6585

8231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

378

756

1134

1512

1890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0208

AC:

3167

AN:

152284

Hom.:

244

Cov.:

AF XY:

0.0263

AC XY:

1961

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0147

AC:

609

AN:

41552

American (AMR)

AF:

0.0378

AC:

578

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0448

AC:

232

AN:

5184

South Asian (SAS)

AF:

0.278

AC:

1342

AN:

4824

European-Finnish (FIN)

AF:

0.0229

AC:

243

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00118

AC:

AN:

68022

Other (OTH)

AF:

0.0299

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

135

269

404

538

673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00845

Hom.:

311

Bravo

AF:

0.0160

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0518

AC:

6288

Asia WGS

AF:

0.215

AC:

745

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Disseminated atypical mycobacterial infection (1)

Immunodeficiency 27A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

5.8

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.34

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0099

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

PhyloP100

0.39

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.11

Sift

Benign

0.12

Sift4G

Benign

0.10

Polyphen

0.26

Vest4

0.10

MPC

0.11

ClinPred

0.021

GERP RS

2.0

Varity_R

0.65

gMVP

0.52

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over