Genetic Variant NM_001329128.2:c.-416A>C (chr21-33403128-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001329128.2(IFNGR2):c.-416A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 143,450 control chromosomes in the GnomAD database, including 5,891 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5889 hom., cov: 26)

Exomes 𝑓: 0.10 ( 2 hom. )

Consequence

IFNGR2
NM_001329128.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.45

Publications

8 publications found

Variant links:

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]

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

IFNGR2 links:

ENSG00000289939 (HGNC:):

ENSG00000289939 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 21-33403128-A-C is Benign according to our data. Variant chr21-33403128-A-C is described in ClinVar as Benign. ClinVar VariationId is 1232698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNGR2	NM_001329128.2 link	c.-416A>C		5_prime_UTR_variant	Exon 1 of 8		NP_001316057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000289939	ENST00000701889.2 link	n.*81A>C		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.249

AC:

35737

AN:

143310

Hom.:

5874

Cov.:

show subpopulations

Gnomad AFR

AF:

0.462

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.132

Gnomad EAS

AF:

0.428

Gnomad SAS

AF:

0.298

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.113

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.211

GnomAD4 exome

AF:

0.102

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0938

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.750

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0606

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.250

AC:

35777

AN:

143362

Hom.:

5889

Cov.:

AF XY:

0.252

AC XY:

17495

AN XY:

69520

show subpopulations

African (AFR)

AF:

0.462

AC:

18031

AN:

38992

American (AMR)

AF:

0.186

AC:

2640

AN:

14170

Ashkenazi Jewish (ASJ)

AF:

0.132

AC:

437

AN:

3308

East Asian (EAS)

AF:

0.428

AC:

2121

AN:

4956

South Asian (SAS)

AF:

0.297

AC:

1341

AN:

4516

European-Finnish (FIN)

AF:

0.209

AC:

1939

AN:

9294

Middle Eastern (MID)

AF:

0.125

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.134

AC:

8728

AN:

65006

Other (OTH)

AF:

0.208

AC:

409

AN:

1964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1167

2334

3501

4668

5835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.176

Hom.:

437

Bravo

AF:

0.252

Asia WGS

AF:

0.362

AC:

1204

AN:

3338

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 20, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

5.8

(source)

DANN

Benign

0.63

PhyloP100

-1.4

PromoterAI

-0.0059

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over