chr6-137218673-G-A

Variant names:

• chr6-137218673-G-A
• rs10457655
• NM_000416.3:c.85+570C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000416.3(IFNGR1):​c.85+570C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 350,342 control chromosomes in the GnomAD database, including 5,516 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3109 hom., cov: 27)
  • Exomes 𝑓: 0.14 (2407 hom.)
• Consequence: IFNGR1 NM_000416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.302 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.85+570C>T		intron	N/A	NP_000407.1
	IFNGR1	NM_001363527.1		c.-40C>T		splice_region	Exon 1 of 7	NP_001350456.1
	IFNGR1	NM_001363527.1		c.-40C>T		5_prime_UTR	Exon 1 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.85+570C>T		intron	N/A	ENSP00000356713.5
	IFNGR1	ENST00000646898.1		c.-58C>T		splice_region	Exon 1 of 8	ENSP00000494069.1
	IFNGR1	ENST00000644894.1		c.-40C>T		splice_region	Exon 1 of 7	ENSP00000495272.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 28760 AN: 142324 Hom.: 3097 Cov.: 27

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.144 AC: 29849 AN: 207948 Hom.: 2407 Cov.: 3 AF XY: 0.136 AC XY: 15526 AN XY: 114086

African (AFR) AF: 0.290 AC: 1594 AN: 5488

American (AMR) AF: 0.118 AC: 1518 AN: 12870

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 1175 AN: 4806

East Asian (EAS) AF: 0.119 AC: 983 AN: 8268

South Asian (SAS) AF: 0.0889 AC: 3946 AN: 44384

European-Finnish (FIN) AF: 0.113 AC: 1013 AN: 8976

Middle Eastern (MID) AF: 0.268 AC: 191 AN: 712

European-Non Finnish (NFE) AF: 0.158 AC: 17760 AN: 112564

Other (OTH) AF: 0.169 AC: 1669 AN: 9880

GnomAD4 genome AF: 0.202 AC: 28796 AN: 142394 Hom.: 3109 Cov.: 27 AF XY: 0.200 AC XY: 13671 AN XY: 68186

African (AFR) AF: 0.307 AC: 11753 AN: 38328

American (AMR) AF: 0.168 AC: 2136 AN: 12706

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 869 AN: 3446

East Asian (EAS) AF: 0.128 AC: 612 AN: 4774

South Asian (SAS) AF: 0.0961 AC: 442 AN: 4598

European-Finnish (FIN) AF: 0.124 AC: 1046 AN: 8426

Middle Eastern (MID) AF: 0.227 AC: 58 AN: 256

European-Non Finnish (NFE) AF: 0.168 AC: 11228 AN: 66978

Other (OTH) AF: 0.227 AC: 449 AN: 1978

Alfa AF: 0.170 Hom.: 2600

Bravo AF: 0.202

Asia WGS AF: 0.130 AC: 453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.4
DANN	Benign	0.84
PhyloP100		-0.53
PromoterAI		-0.020	Neutral
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: rs10457655; hg19: chr6-137539810; COSMIC: COSV62989439;