6-137219233-A-G

Variant names:

• chr6-137219233-A-G
• rs7749390
• NM_000416.3:c.85+10T>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.85+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,602,902 control chromosomes in the GnomAD database, including 138,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14807 hom., cov: 32)
  • Exomes 𝑓: 0.41 (123435 hom.)
• Consequence: IFNGR1 NM_000416.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.0250
• Publications: 46 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 (BayesDel_noAF=-0.85).
• BP6: Variant 6-137219233-A-G is Benign according to our data. Variant chr6-137219233-A-G is described in ClinVar as Benign. ClinVar VariationId is 355562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.61 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	NM_000416.3	MANE Select	c.85+10T>C		intron	N/A	NP_000407.1
	IFNGR1	NM_001363526.1		c.-306T>C		upstream_gene	N/A	NP_001350455.1
	IFNGR1	NM_001363527.1		c.-600T>C		upstream_gene	N/A	NP_001350456.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.85+10T>C		intron	N/A	ENSP00000356713.5
	IFNGR1	ENST00000644894.1		c.-600T>C		5_prime_UTR	Exon 1 of 7	ENSP00000495272.1
	IFNGR1	ENST00000957752.1		c.85+10T>C		intron	N/A	ENSP00000627811.1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66181 AN: 151938 Hom.: 14762 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.469

GnomAD2 exomes AF: 0.431 AC: 98680 AN: 229126 AF XY: 0.440

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.500

Gnomad EAS exome AF: 0.577

Gnomad FIN exome AF: 0.362

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.407 AC: 590179 AN: 1450846 Hom.: 123435 Cov.: 41 AF XY: 0.413 AC XY: 297737 AN XY: 720686

African (AFR) AF: 0.516 AC: 17211 AN: 33372

American (AMR) AF: 0.359 AC: 15441 AN: 43058

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 12821 AN: 25756

East Asian (EAS) AF: 0.541 AC: 21246 AN: 39256

South Asian (SAS) AF: 0.605 AC: 51011 AN: 84368

European-Finnish (FIN) AF: 0.365 AC: 19082 AN: 52296

Middle Eastern (MID) AF: 0.495 AC: 2722 AN: 5496

European-Non Finnish (NFE) AF: 0.383 AC: 424508 AN: 1107324

Other (OTH) AF: 0.436 AC: 26137 AN: 59920

GnomAD4 genome AF: 0.436 AC: 66286 AN: 152056 Hom.: 14807 Cov.: 32 AF XY: 0.439 AC XY: 32657 AN XY: 74342

African (AFR) AF: 0.506 AC: 20980 AN: 41464

American (AMR) AF: 0.394 AC: 6025 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1752 AN: 3468

East Asian (EAS) AF: 0.577 AC: 2972 AN: 5148

South Asian (SAS) AF: 0.628 AC: 3034 AN: 4830

European-Finnish (FIN) AF: 0.354 AC: 3744 AN: 10586

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26260 AN: 67968

Other (OTH) AF: 0.471 AC: 991 AN: 2106

Alfa AF: 0.403 Hom.: 14759

Bravo AF: 0.435

Asia WGS AF: 0.631 AC: 2191 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 27A (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency (1)
-	-	1	Disseminated atypical mycobacterial infection (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.5
DANN	Benign	0.66
PhyloP100		0.025
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs7749390; hg19: chr6-137540370;