chr6-137206134-A-G

Variant names:

• chr6-137206134-A-G
• rs1554227230
• NM_000416.3:c.373+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_000416.3(IFNGR1):​c.373+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000636215: Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID:10480427). Studies have shown that disruption of this splice site alters IFNGR1 gene expression (PMID:10480427).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFNGR1 NM_000416.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.86
• Publications: 0 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000636215: Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 10480427). Studies have shown that disruption of this splice site alters IFNGR1 gene expression (PMID: 10480427).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-137206134-A-G is Pathogenic according to our data. Variant chr6-137206134-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 462774.Status of the report is criteria_provided_single_submitter, 1 stars.

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.373+2T>C		splice_donor intron	N/A	NP_000407.1	A0A0S2Z3Y2
	IFNGR1	NM_001363526.1		c.343+2T>C		splice_donor intron	N/A	NP_001350455.1	A0A2R8Y4U4
	IFNGR1	NM_001363527.1		c.250+2T>C		splice_donor intron	N/A	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.373+2T>C		splice_donor intron	N/A	ENSP00000356713.5	P15260-1
	IFNGR1	ENST00000957752.1		c.373+2T>C		splice_donor intron	N/A	ENSP00000627811.1
	IFNGR1	ENST00000414770.6	TSL:3	c.343+2T>C		splice_donor intron	N/A	ENSP00000394230.2	A0A2R8Y4U4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.9
GERP RS		5.7
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554227230; hg19: chr6-137527271;