Genetic Variant NM_002198.3:c.854-33C>T (chr5-132484108-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002198.3(IRF1):c.854-33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,607,370 control chromosomes in the GnomAD database, including 96,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.38 ( 11107 hom., cov: 31)

Exomes 𝑓: 0.34 ( 85204 hom. )

Consequence

IRF1
NM_002198.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.362

Publications

16 publications found

Variant links:

Genes affected

IRF1 (HGNC:6116): (interferon regulatory factor 1) The protein encoded by this gene is a transcriptional regulator and tumor suppressor, serving as an activator of genes involved in both innate and acquired immune responses. The encoded protein activates the transcription of genes involved in the body's response to viruses and bacteria, playing a role in cell proliferation, apoptosis, the immune response, and DNA damage response. This protein represses the transcription of several other genes. As a tumor suppressor, it both suppresses tumor cell growth and stimulates an immune response against tumor cells. Defects in this gene have been associated with gastric cancer, myelogenous leukemia, and lung cancer. [provided by RefSeq, Aug 2017]

IRF1 links:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

CARINH (HGNC:33838): (colitis associated IRF1 antisense regulator of intestinal homeostasis)

CARINH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 5-132484108-G-A is Benign according to our data. Variant chr5-132484108-G-A is described in ClinVar as Benign. ClinVar VariationId is 2688379.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF1	NM_002198.3 link	c.854-33C>T		intron_variant	Intron 9 of 9	ENST00000245414.9	NP_002189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF1	ENST00000245414.9 link	c.854-33C>T		intron_variant	Intron 9 of 9	1	NM_002198.3	ENSP00000245414.4
ENSG00000283782	ENST00000638452.2 link	c.-169+34419G>A		intron_variant	Intron 3 of 26	5		ENSP00000492349.2

Frequencies

GnomAD3 genomes

AF:

0.377

AC:

57105

AN:

151544

Hom.:

11093

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.360

Gnomad SAS

AF:

0.409

Gnomad FIN

AF:

0.326

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.358

GnomAD2 exomes

AF:

0.347

AC:

86691

AN:

249788

AF XY:

0.346

show subpopulations

Gnomad AFR exome

AF:

0.486

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.313

Gnomad EAS exome

AF:

0.344

Gnomad FIN exome

AF:

0.326

Gnomad NFE exome

AF:

0.329

Gnomad OTH exome

AF:

0.354

GnomAD4 exome

AF:

0.340

AC:

494527

AN:

1455708

Hom.:

85204

Cov.:

AF XY:

0.341

AC XY:

246456

AN XY:

723688

show subpopulations

African (AFR)

AF:

0.491

AC:

16384

AN:

33362

American (AMR)

AF:

0.331

AC:

14757

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

8104

AN:

25994

East Asian (EAS)

AF:

0.331

AC:

13077

AN:

39560

South Asian (SAS)

AF:

0.387

AC:

33280

AN:

86016

European-Finnish (FIN)

AF:

0.329

AC:

17525

AN:

53282

Middle Eastern (MID)

AF:

0.400

AC:

2231

AN:

5572

European-Non Finnish (NFE)

AF:

0.333

AC:

368257

AN:

1107184

Other (OTH)

AF:

0.348

AC:

20912

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

14367

28733

43100

57466

71833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12140

24280

36420

48560

60700

<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:

0.377

AC:

57162

AN:

151662

Hom.:

11107

Cov.:

AF XY:

0.376

AC XY:

27856

AN XY:

74106

show subpopulations

African (AFR)

AF:

0.485

AC:

20037

AN:

41296

American (AMR)

AF:

0.342

AC:

5219

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1106

AN:

3468

East Asian (EAS)

AF:

0.359

AC:

1851

AN:

5158

South Asian (SAS)

AF:

0.410

AC:

1973

AN:

4816

European-Finnish (FIN)

AF:

0.326

AC:

3419

AN:

10494

Middle Eastern (MID)

AF:

0.486

AC:

143

AN:

294

European-Non Finnish (NFE)

AF:

0.331

AC:

22454

AN:

67862

Other (OTH)

AF:

0.358

AC:

752

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1804

3609

5413

7218

9022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

548

1096

1644

2192

2740

<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:

0.348

Hom.:

3344

Bravo

AF:

0.381

Asia WGS

AF:

0.376

AC:

1308

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.8

(source)

DANN

Benign

0.43

PhyloP100

-0.36

PromoterAI

-0.026

Neutral

(source)

Mutation Taster

=100/0

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