NM_000416.3:c.182T>A

Variant names:

• chr6-137206981-A-T
• rs121912715
• NM_000416.3:c.182T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000416.3(IFNGR1):​c.182T>A​(p.Val61Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V61I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFNGR1 NM_000416.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.09
• Publications: 5 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 6-137206981-A-T is Pathogenic according to our data. Variant chr6-137206981-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 17950.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNGR1	NM_000416.3	c.182T>A	p.Val61Glu	missense_variant	Exon 2 of 7	ENST00000367739.9	NP_000407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNGR1	ENST00000367739.9	c.182T>A	p.Val61Glu	missense_variant	Exon 2 of 7	1	NM_000416.3	ENSP00000356713.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency 27A Pathogenic:1

May 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;.;.;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.64	T;.;T;.;.;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;.;.
PhyloP100		1.1
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.8	D;.;.;.;.;.;.;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;.;.;.;.;.;.;D;D
Sift4G	Uncertain	0.0080	D;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.92		Gain of disorder (P = 0.0304);.;.;.;.;.;.;Gain of disorder (P = 0.0304);.;
MVP		0.96
MPC		0.39
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.96
gMVP		0.99
Mutation Taster		=22/78	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912715; hg19: chr6-137528118;