Genetic Variant IFNGR1:p.Val14Leu (chr6-137219288-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000416.3(IFNGR1):c.40G>C(p.Val14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V14M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IFNGR1
NM_000416.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0310

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19860804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNGR1	NM_000416.3 link	c.40G>C	p.Val14Leu	missense_variant	Exon 1 of 7	ENST00000367739.9	NP_000407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNGR1	ENST00000367739.9 link	c.40G>C	p.Val14Leu	missense_variant	Exon 1 of 7	1	NM_000416.3	ENSP00000356713.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459528

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.00

AC:

AN:

39598

South Asian (SAS)

AF:

0.00

AC:

AN:

85640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111172

Other (OTH)

AF:

0.00

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.30

CADD

Benign

2.6

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.0

L;.

PhyloP100

-0.031

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.40

N;N

REVEL

Benign

0.24

Sift

Benign

0.23

T;T

Sift4G

Benign

0.26

T;.

Polyphen

0.45

B;.

Vest4

0.072

MutPred

0.55

Loss of catalytic residue at V14 (P = 0.0419);Loss of catalytic residue at V14 (P = 0.0419);

MVP

0.84

MPC

0.064

ClinPred

0.17

GERP RS

1.4

PromoterAI

0.0062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.070

gMVP

0.52

Mutation Taster

=294/6

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over