Genetic Variant IRF1:p.Met8Leu (chr5-132489457-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1PM2

The NM_002198.3(IRF1):c.22A>C(p.Met8Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IRF1
NM_002198.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.07

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PS1

Transcript NM_002198.3 (IRF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF1	NM_002198.3 link	c.22A>C	p.Met8Leu	missense_variant	Exon 2 of 10	ENST00000245414.9	NP_002189.1	P10914Q6FHN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF1	ENST00000245414.9 link	c.22A>C	p.Met8Leu	missense_variant	Exon 2 of 10	1	NM_002198.3	ENSP00000245414.4		P10914
ENSG00000283782	ENST00000638452.2 link	c.-169+39768T>G		intron_variant	Intron 3 of 26	5		ENSP00000492349.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111922

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.82

D;D;D;.;D;.

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

.;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.66

D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.90

L;L;.;.;.;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.8

D;D;.;D;D;.

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;D;.;T;T;.

Sift4G

Pathogenic

0.0

D;D;T;T;.;.

Polyphen

0.035

B;B;.;.;.;.

Vest4

0.65

MutPred

0.62

Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);

MVP

0.90

MPC

1.7

ClinPred

0.89

GERP RS

5.6

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.85

gMVP

0.91

Mutation Taster

=6/94

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over