21-33403580-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_005534.4(IFNGR2):c.37C>T(p.Leu13Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,375,618 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: IFNGR2 NM_005534.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.472

Genes affected

IFNGR2 (HGNC:5440): (interferon gamma receptor 2) This gene (IFNGR2) encodes the non-ligand-binding beta chain of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. Defects in IFNGR2 are a cause of mendelian susceptibility to mycobacterial disease (MSMD), also known as familial disseminated atypical mycobacterial infection. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.071060866).
• BP6: Variant 21-33403580-C-T is Benign according to our data. Variant chr21-33403580-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr21-33403580-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00121 (183/151254) while in subpopulation AMR AF= 0.00329 (50/15210). AF 95% confidence interval is 0.00256. There are 1 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR2	NM_005534.4	c.37C>T	p.Leu13Phe	missense_variant	1/7	ENST00000290219.11
IFNGR2	NM_001329128.2	c.37C>T	p.Leu13Phe	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR2	ENST00000290219.11	c.37C>T	p.Leu13Phe	missense_variant	1/7	1	NM_005534.4	P1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 183 AN: 151146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00329

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00126 AC: 77 AN: 60948 Hom.: 1 AF XY: 0.00122 AC XY: 44 AN XY: 36016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.000350

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000278

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00325

GnomAD4 exome AF: 0.00163 AC: 1996 AN: 1224364 Hom.: 4 Cov.: 31 AF XY: 0.00154 AC XY: 928 AN XY: 601066

Gnomad4 AFR exome AF: 0.000243

Gnomad4 AMR exome AF: 0.00243

Gnomad4 ASJ exome AF: 0.000447

Gnomad4 EAS exome AF: 0.000116

Gnomad4 SAS exome AF: 0.000289

Gnomad4 FIN exome AF: 0.0000690

Gnomad4 NFE exome AF: 0.00186

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00121 AC: 183 AN: 151254 Hom.: 1 Cov.: 32 AF XY: 0.00104 AC XY: 77 AN XY: 73928

Gnomad4 AFR AF: 0.000531

Gnomad4 AMR AF: 0.00329

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.37C>T (p.L13F) alteration is located in exon 1 (coding exon 1) of the IFNGR2 gene. This alteration results from a C to T substitution at nucleotide position 37, causing the leucine (L) at amino acid position 13 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Immunodeficiency 28 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2022

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 13 of the IFNGR2 protein (p.Leu13Phe). This variant is present in population databases (no rsID available, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with IFNGR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 474968). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

IFNGR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	12
Dann	Benign	0.94
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.41	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.81	N;N
REVEL	Benign	0.18
Sift	Benign	0.20	T;T
Sift4G	Benign	0.25	T;D
Polyphen		1.0	D;D
Vest4		0.28
MVP		0.79
MPC		0.43
ClinPred		0.048	T
GERP RS		1.2
Varity_R		0.11
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs1012938610; hg19: chr21-34775886;