NM_000416.3:c.1004A>C

Variant names:

• chr6-137198497-T-G
• rs17175350
• NM_000416.3:c.1004A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000416.3(IFNGR1):​c.1004A>C​(p.His335Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,614,194 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (3 hom.)
• Consequence: IFNGR1 NM_000416.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.230
• Publications: 8 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• immunodeficiency 27A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039782524).
• BP6: Variant 6-137198497-T-G is Benign according to our data. Variant chr6-137198497-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00392 (597/152328) while in subpopulation AFR AF = 0.0136 (567/41566). AF 95% confidence interval is 0.0127. There are 4 homozygotes in GnomAd4. There are 280 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	NM_000416.3	MANE Select	c.1004A>C	p.His335Pro	missense	Exon 7 of 7	NP_000407.1	A0A0S2Z3Y2
	IFNGR1	NM_001363526.1		c.974A>C	p.His325Pro	missense	Exon 8 of 8	NP_001350455.1	A0A2R8Y4U4
	IFNGR1	NM_001363527.1		c.881A>C	p.His294Pro	missense	Exon 7 of 7	NP_001350456.1	A0A2R8YFL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.1004A>C	p.His335Pro	missense	Exon 7 of 7	ENSP00000356713.5	P15260-1
	IFNGR1	ENST00000957752.1		c.998A>C	p.His333Pro	missense	Exon 7 of 7	ENSP00000627811.1
	IFNGR1	ENST00000414770.6	TSL:3	c.974A>C	p.His325Pro	missense	Exon 8 of 8	ENSP00000394230.2	A0A2R8Y4U4

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152210 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.0000147

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00107 AC: 269 AN: 251328 AF XY: 0.000729

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000461 AC: 674 AN: 1461866 Hom.: 3 Cov.: 32 AF XY: 0.000393 AC XY: 286 AN XY: 727236

African (AFR) AF: 0.0167 AC: 560 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112006

Other (OTH) AF: 0.00108 AC: 65 AN: 60396

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152328 Hom.: 4 Cov.: 31 AF XY: 0.00376 AC XY: 280 AN XY: 74498

African (AFR) AF: 0.0136 AC: 567 AN: 41566

American (AMR) AF: 0.00137 AC: 21 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00188 Hom.: 8

Bravo AF: 0.00498

ESP6500AA AF: 0.0163 AC: 72

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00132 AC: 160

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Disseminated atypical mycobacterial infection (1)
-	-	1	Immunodeficiency 27A (1)
-	-	1	Interferon gamma receptor deficiency (1)
-	-	1	Mycobacterium tuberculosis, susceptibility to;C1838332:Helicobacter pylori infection, susceptibility to;C1864880:Hepatitis B virus, susceptibility to;C4011949:Immunodeficiency 27A;C4014863:Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.3
DANN	Benign	0.72
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.45	N
PhyloP100		-0.23
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.042
Sift	Benign	0.20	T
Sift4G	Benign	0.26	T
Polyphen		0.0020	B
Vest4		0.057
MVP		0.61
MPC		0.074
ClinPred		0.0047	T
GERP RS		-0.20
Varity_R		0.21
gMVP		0.13
Mutation Taster		=90/10	polymorphism

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: rs17175350; hg19: chr6-137519634;