rs121913215

Variant names:

• chr21-33432623-A-T
• rs121913215
• NM_005534.4:c.722-91A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_005534.4(IFNGR2):​c.722-91A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,411,940 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 not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: IFNGR2 NM_005534.4 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.194
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00116 (176/152288) while in subpopulation AMR AF = 0.00236 (36/15286). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005534.4. 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
	IFNGR2	NM_005534.4	MANE Select	c.722-91A>T		intron	N/A	NP_005525.2
	IFNGR2	NM_001329128.2		c.779-91A>T		intron	N/A	NP_001316057.1	E7EUY1
	TMEM50B	NR_040016.2		n.2955T>A		non_coding_transcript_exon	Exon 9 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.722-91A>T		intron	N/A	ENSP00000290219.5	P38484
	TMEM50B	ENST00000420455.5	TSL:1	n.*2300T>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000397773.1	P56557
	TMEM50B	ENST00000420455.5	TSL:1	n.*2300T>A		3_prime_UTR	Exon 9 of 9	ENSP00000397773.1	P56557

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00144 AC: 1810 AN: 1259652 Hom.: 2 Cov.: 18 AF XY: 0.00150 AC XY: 958 AN XY: 637204

African (AFR) AF: 0.000614 AC: 18 AN: 29332

American (AMR) AF: 0.00101 AC: 45 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00684 AC: 170 AN: 24842

East Asian (EAS) AF: 0.00 AC: 0 AN: 38750

South Asian (SAS) AF: 0.00191 AC: 157 AN: 82340

European-Finnish (FIN) AF: 0.000249 AC: 13 AN: 52228

Middle Eastern (MID) AF: 0.00390 AC: 21 AN: 5382

European-Non Finnish (NFE) AF: 0.00138 AC: 1283 AN: 928474

Other (OTH) AF: 0.00191 AC: 103 AN: 53852

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74462

African (AFR) AF: 0.000241 AC: 10 AN: 41560

American (AMR) AF: 0.00236 AC: 36 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000847 Hom.: 0

Bravo AF: 0.00168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.80
PhyloP100		-0.19
PromoterAI		-0.026	Neutral
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: rs121913215; hg19: chr21-34804930;