21-33432659-T-C

Variant names:

• chr21-33432659-T-C
• rs1532
• ENST00000420455.5:n.*2264A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000420455.5(TMEM50B):​n.*2264A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 1,579,122 control chromosomes in the GnomAD database, including 424,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45996 hom., cov: 31)
  • Exomes 𝑓: 0.73 (378207 hom.)
• Consequence: TMEM50B ENST00000420455.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.43
• Publications: 21 publications found

Genes affected

TMEM50B (HGNC:1280): (transmembrane protein 50B) Predicted to be involved in late endosome to vacuole transport via multivesicular body sorting pathway. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

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]

IFNGR2 Gene-Disease associations (from GenCC):

• immunodeficiency 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 21-33432659-T-C is Benign according to our data. Variant chr21-33432659-T-C is described in ClinVar as Benign. ClinVar VariationId is 1268638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000420455.5. 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
	IFNGR2	NM_005534.4	MANE Select	c.722-55T>C		intron	N/A	NP_005525.2
	TMEM50B	NR_040016.2		n.2919A>G		non_coding_transcript_exon	Exon 9 of 9
	IFNGR2	NM_001329128.2		c.779-55T>C		intron	N/A	NP_001316057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM50B	ENST00000420455.5	TSL:1	n.*2264A>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000397773.1
	TMEM50B	ENST00000420455.5	TSL:1	n.*2264A>G		3_prime_UTR	Exon 9 of 9	ENSP00000397773.1
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.722-55T>C		intron	N/A	ENSP00000290219.5

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117515 AN: 152032 Hom.: 45937 Cov.: 31

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.743

GnomAD4 exome AF: 0.725 AC: 1034793 AN: 1426972 Hom.: 378207 Cov.: 25 AF XY: 0.724 AC XY: 515612 AN XY: 712186

African (AFR) AF: 0.870 AC: 28512 AN: 32768

American (AMR) AF: 0.852 AC: 38092 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 16689 AN: 25880

East Asian (EAS) AF: 0.976 AC: 38599 AN: 39530

South Asian (SAS) AF: 0.765 AC: 65474 AN: 85586

European-Finnish (FIN) AF: 0.788 AC: 41942 AN: 53256

Middle Eastern (MID) AF: 0.682 AC: 3893 AN: 5708

European-Non Finnish (NFE) AF: 0.702 AC: 757915 AN: 1080212

Other (OTH) AF: 0.736 AC: 43677 AN: 59340

GnomAD4 genome AF: 0.773 AC: 117631 AN: 152150 Hom.: 45996 Cov.: 31 AF XY: 0.780 AC XY: 58008 AN XY: 74372

African (AFR) AF: 0.866 AC: 35958 AN: 41538

American (AMR) AF: 0.814 AC: 12426 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2234 AN: 3468

East Asian (EAS) AF: 0.984 AC: 5085 AN: 5170

South Asian (SAS) AF: 0.776 AC: 3745 AN: 4828

European-Finnish (FIN) AF: 0.794 AC: 8406 AN: 10582

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.698 AC: 47421 AN: 67978

Other (OTH) AF: 0.744 AC: 1572 AN: 2112

Alfa AF: 0.719 Hom.: 19868

Bravo AF: 0.781

Asia WGS AF: 0.890 AC: 3096 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 92% of patients studied by a panel of primary immunodeficiencies. Number of patients: 81. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.37
DANN	Benign	0.36
PhyloP100		-1.4
PromoterAI		0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1532; hg19: chr21-34804966;