Genetic Variant NM_002198.3:c.31T>C (chr5-132489448-A-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_002198.3(IRF1):c.31T>C(p.Trp11Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

IRF1
NM_002198.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.13

Publications

9 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 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 5-132489448-A-G is Pathogenic according to our data. Variant chr5-132489448-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 14721.Status of the report is no_assertion_criteria_provided, 0 stars.

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	HGVSp	Effect	Exon Rank	Protein
IRF1	NM_002198.3	MANE Select	c.31T>C	p.Trp11Arg	missense	Exon 2 of 10	NP_002189.1
IRF1	NM_001354924.1		c.31T>C	p.Trp11Arg	missense	Exon 2 of 9	NP_001341853.1
IRF1	NM_001354925.1		c.31T>C	p.Trp11Arg	missense	Exon 2 of 8	NP_001341854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IRF1	ENST00000245414.9	TSL:1 MANE Select	c.31T>C	p.Trp11Arg	missense	Exon 2 of 10	ENSP00000245414.4
IRF1	ENST00000493208.1	TSL:1	n.246T>C		non_coding_transcript_exon	Exon 2 of 2
IRF1	ENST00000613424.5	TSL:1	n.31T>C		non_coding_transcript_exon	Exon 2 of 8	ENSP00000480887.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Non-small cell lung carcinoma

Pathogenic:1

Jul 07, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.4

PhyloP100

9.1

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-13

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.88

Gain of disorder (P = 3e-04)

MVP

0.99

MPC

2.3

ClinPred

1.0

GERP RS

5.6

PromoterAI

-0.063

Neutral

(source)

Varity_R

0.99

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over