NM_005534.4:c.514T>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_005534.4(IFNGR2):c.514T>G(p.Phe172Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,611,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F172I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

IFNGR2
NM_005534.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.908

Publications

1 publications found

Variant links:

Genes affected

IFNGR2 (HGNC:5440): (interferon gamma receptor 2) This gene (IFNGR2) encodes the non-ligand-binding beta chain of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. Defects in IFNGR2 are a cause of mendelian susceptibility to mycobacterial disease (MSMD), also known as familial disseminated atypical mycobacterial infection. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance. [provided by RefSeq, Jul 2008]

IFNGR2 Gene-Disease associations (from GenCC):

immunodeficiency 28
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IFNGR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04581049).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000046 (7/152032) while in subpopulation AFR AF = 0.000169 (7/41396). AF 95% confidence interval is 0.000079. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005534.4. 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
	IFNGR2	NM_005534.4	MANE Select	c.514T>G	p.Phe172Val	missense	Exon 4 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.571T>G	p.Phe191Val	missense	Exon 5 of 8	NP_001316057.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.514T>G	p.Phe172Val	missense	Exon 4 of 7	ENSP00000290219.5
IFNGR2	ENST00000381995.5	TSL:5	c.571T>G	p.Phe191Val	missense	Exon 5 of 8	ENSP00000371425.1
IFNGR2	ENST00000696724.1		c.505T>G	p.Phe169Val	missense	Exon 4 of 7	ENSP00000512835.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251326

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459048

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726010

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33406

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109468

Other (OTH)

AF:

0.0000166

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency 28

Uncertain:1

Mar 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 172 of the IFNGR2 protein (p.Phe172Val). This variant is present in population databases (rs375419913, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with IFNGR2-related conditions.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.044

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.059

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.46

M_CAP

Benign

0.0054

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

-0.91

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.42

REVEL

Benign

0.022

Sift

Benign

0.50

Sift4G

Benign

0.50

Polyphen

0.042

Vest4

0.077

MVP

0.29

MPC

0.54

ClinPred

0.034

GERP RS

-9.7

Varity_R

0.17

gMVP

0.41

Mutation Taster

=91/9

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over