6-137219399-G-A

Variant names:

• chr6-137219399-G-A
• rs17181457
• ENST00000414770.6:c.-213C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000414770.6(IFNGR1):​c.-213C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,554,488 control chromosomes in the GnomAD database, including 4,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (279 hom., cov: 33)
  • Exomes 𝑓: 0.070 (3847 hom.)
• Consequence: IFNGR1 ENST00000414770.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.49
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-137219399-G-A is Benign according to our data. Variant chr6-137219399-G-A is described in ClinVar as Benign. ClinVar VariationId is 355566.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000414770.6. 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.-72C>T		upstream_gene	N/A	NP_000407.1	A0A0S2Z3Y2
	IFNGR1	NM_001363526.1		c.-472C>T		upstream_gene	N/A	NP_001350455.1	A0A2R8Y4U4
	IFNGR1	NM_001363527.1		c.-766C>T		upstream_gene	N/A	NP_001350456.1	A0A2R8YFL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000414770.6	TSL:3	c.-213C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000394230.2	A0A2R8Y4U4
	IFNGR1	ENST00000911309.1		c.-72C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000581368.1
	IFNGR1	ENST00000458076.6	TSL:3	c.-72C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000389249.2	Q5TFC9

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7910 AN: 152194 Hom.: 280 Cov.: 33

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0534

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0670

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.0502

GnomAD4 exome AF: 0.0697 AC: 97793 AN: 1402178 Hom.: 3847 Cov.: 33 AF XY: 0.0690 AC XY: 47710 AN XY: 691944

African (AFR) AF: 0.0109 AC: 348 AN: 32002

American (AMR) AF: 0.0396 AC: 1417 AN: 35824

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3145 AN: 25120

East Asian (EAS) AF: 0.000634 AC: 23 AN: 36286

South Asian (SAS) AF: 0.0472 AC: 3750 AN: 79486

European-Finnish (FIN) AF: 0.0709 AC: 3476 AN: 49054

Middle Eastern (MID) AF: 0.0672 AC: 371 AN: 5520

European-Non Finnish (NFE) AF: 0.0754 AC: 81476 AN: 1080778

Other (OTH) AF: 0.0652 AC: 3787 AN: 58108

GnomAD4 genome AF: 0.0519 AC: 7907 AN: 152310 Hom.: 279 Cov.: 33 AF XY: 0.0512 AC XY: 3810 AN XY: 74484

African (AFR) AF: 0.0129 AC: 536 AN: 41572

American (AMR) AF: 0.0534 AC: 817 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.0449 AC: 217 AN: 4830

European-Finnish (FIN) AF: 0.0670 AC: 711 AN: 10614

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0738 AC: 5022 AN: 68020

Other (OTH) AF: 0.0492 AC: 104 AN: 2114

Alfa AF: 0.0247 Hom.: 11

Bravo AF: 0.0484

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 27A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.21
DANN	Benign	0.75
PhyloP100		-2.5
PromoterAI		-0.15	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs17181457; hg19: chr6-137540536;