Genetic Variant IRF1:c.-6+395A>C (chr5-132490150-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002198.3(IRF1):c.-6+395A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 152,194 control chromosomes in the GnomAD database, including 21,004 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.52 ( 20996 hom., cov: 33)

Exomes 𝑓: 0.39 ( 8 hom. )

Consequence

IRF1
NM_002198.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0250

Publications

24 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 Gene-Disease associations (from GenCC):

immunodeficiency 117
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

IRF1 links:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002198.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002198.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRF1	NM_002198.3	MANE Select	c.-6+395A>C	intron	N/A	NP_002189.1	P10914
IRF1	NM_001354924.1		c.-6+395A>C	intron	N/A	NP_001341853.1	X5D3F6
IRF1	NM_001354925.1		c.-6+395A>C	intron	N/A	NP_001341854.1	A0A7P0TAL6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRF1	ENST00000245414.9	TSL:1 MANE Select	c.-6+395A>C	intron	N/A	ENSP00000245414.4	P10914
ENSG00000283782	ENST00000638452.2	TSL:5	c.-169+40461T>G	intron	N/A	ENSP00000492349.2	A0A1W2PQ90
IRF1	ENST00000493208.1	TSL:1	n.210+395A>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.517

AC:

78611

AN:

151966

Hom.:

20958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.324

Gnomad AMR

AF:

0.548

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.698

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.500

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.487

GnomAD4 exome

AF:

0.391

AC:

AN:

110

Hom.:

Cov.:

AF XY:

0.395

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

0.200

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.397

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.518

AC:

78710

AN:

152084

Hom.:

20996

Cov.:

AF XY:

0.525

AC XY:

39032

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.622

AC:

25798

AN:

41490

American (AMR)

AF:

0.548

AC:

8377

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

1431

AN:

3464

East Asian (EAS)

AF:

0.698

AC:

3602

AN:

5164

South Asian (SAS)

AF:

0.615

AC:

2969

AN:

4828

European-Finnish (FIN)

AF:

0.500

AC:

5293

AN:

10590

Middle Eastern (MID)

AF:

0.605

AC:

178

AN:

294

European-Non Finnish (NFE)

AF:

0.438

AC:

29733

AN:

67936

Other (OTH)

AF:

0.489

AC:

1035

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

1983

3966

5949

7932

9915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

692

1384

2076

2768

3460

<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:

0.394

Hom.:

2000

Bravo

AF:

0.522

Asia WGS

AF:

0.618

AC:

2149

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.7

(source)

DANN

Benign

0.39

PhyloP100

0.025

PromoterAI

0.042

Neutral

(source)

Mutation Taster

=299/1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over