chr6-137203623-C-T

Variant names:

• chr6-137203623-C-T
• rs201471898
• NM_000416.3:c.609G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000416.3(IFNGR1):​c.609G>A​(p.Ala203Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,612,028 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: IFNGR1 NM_000416.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.16
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-137203623-C-T is Benign according to our data. Variant chr6-137203623-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 531672.
• BP7: Synonymous conserved (PhyloP=-3.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000269 (41/152142) while in subpopulation SAS AF = 0.00104 (5/4826). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.609G>A	p.Ala203Ala	synonymous	Exon 5 of 7	NP_000407.1
	IFNGR1	NM_001363526.1		c.579G>A	p.Ala193Ala	synonymous	Exon 6 of 8	NP_001350455.1
	IFNGR1	NM_001363527.1		c.486G>A	p.Ala162Ala	synonymous	Exon 5 of 7	NP_001350456.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.609G>A	p.Ala203Ala	synonymous	Exon 5 of 7	ENSP00000356713.5
	IFNGR1	ENST00000957752.1		c.603G>A	p.Ala201Ala	synonymous	Exon 5 of 7	ENSP00000627811.1
	IFNGR1	ENST00000414770.6	TSL:3	c.579G>A	p.Ala193Ala	synonymous	Exon 6 of 8	ENSP00000394230.2

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000402 AC: 101 AN: 251306 AF XY: 0.000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000283 AC: 413 AN: 1459886 Hom.: 2 Cov.: 30 AF XY: 0.000290 AC XY: 211 AN XY: 726416

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.000246 AC: 11 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86194

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53412

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.000231 AC: 257 AN: 1110256

Other (OTH) AF: 0.000398 AC: 24 AN: 60314

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41502

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10566

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

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000589 Hom.: 0

Bravo AF: 0.000287

EpiCase AF: 0.000709

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.1
DANN	Benign	0.27
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs201471898; hg19: chr6-137524760;