NM_000416.3:c.1400T>C

Variant names:

• chr6-137198101-A-G
• rs1887415
• NM_000416.3:c.1400T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.394
• Publications: 32 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 32

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

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.: 31 AF XY: 0.0280 AC XY: 20347 AN XY: 727230

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: 92 AN: 5768

European-Non Finnish (NFE) AF: 0.000762 AC: 847 AN: 1111996

Other (OTH) AF: 0.0285 AC: 1722 AN: 60394

GnomAD4 genome AF: 0.0208 AC: 3167 AN: 152284 Hom.: 244 Cov.: 32 AF XY: 0.0263 AC XY: 1961 AN XY: 74460

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: 20 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: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68022

Other (OTH) AF: 0.0299 AC: 63 AN: 2108

Alfa AF: 0.00845 Hom.: 311

Bravo AF: 0.0160

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.000930 AC: 8

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

Pathogenic	VUS	Benign	Condition
-	-	1	Disseminated atypical mycobacterial infection (1)
-	-	1	Immunodeficiency 27A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.8
DANN	Benign	0.93
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.39
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.11
Sift	Benign	0.12	T
Sift4G	Benign	0.10	T
Polyphen		0.26	B
Vest4		0.10
MPC		0.11
ClinPred		0.021	T
GERP RS		2.0
Varity_R		0.65
gMVP		0.52
Mutation Taster		=91/9	polymorphism (auto)

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: rs1887415; hg19: chr6-137519238; COSMIC: COSV62992036;